Retroviral protease inhibiting compounds

ABSTRACT

A retroviral protease inhibiting compound of the formula A--X--B is disclosed. Also disclosed are a composition and method for inhibiting a retroviral protease and for treating an HIV infection. Also disclosed are processes and intermediates useful for the preparation of the retroviral protease inhibitors.

This invention was made with Government support under contract numberAI27220 awarded by the National Institute of Allergy and InfectiousDiseases. The Government has certain rights in this invention.

This application is a division of U.S. patent application Ser. No.08/270,210, filed Aug. 23, 1994, now abandoned, which is a division ofU.S. patent application Ser. No. 08/121,673, filed Sep. 14, 1993 (nowU.S. Pat. No. 5,354,866), which is a continuation of U.S. patentapplication Ser. No. 07/777,626, filed Oct. 23, 1991 (now abandoned),which is a continuation-in-part of U.S. patent application Ser. No.07/746,020, filed Aug. 15, 1991 (now abandoned), which is acontinuation-in-part of U.S. patent application Ser. No. 07/616,170,filed Nov. 20, 1990 (now abandoned), which is a continuation-in-part ofU.S. patent application Ser. No. 07/518,730, filed May 9, 1990 (now U.S.Pat. No. 5,142,056), which is a continuation-in-part of U.S. patentapplication Ser. No. 07/456,124, filed Dec. 22, 1989 (now abandoned),which is a continuation-in-part of U.S. patent application Ser. No.07/405,604, filed Sep. 8, 1989 (now abandoned), which is acontinuation-in-part of U.S. patent application Ser. No. 07/355,945,filed May 23, 1989 (now abandoned).

TECHNICAL FIELD

The present invention relates to novel compounds and a composition andmethod for inhibiting retroviral proteases and in particular forinhibiting human immunodeficiency virus (HIV) protease, a compositionand method for treating a retroviral infection and in particular an HIVinfection, processes for making such compounds and syntheticintermediates employed in these processes.

BACKGROUND ART

Retroviruses are those viruses which utilize a ribonucleic acid (RNA)intermediate and a RNA-dependent deoxyribonucleic acid (DNA) polymerase,reverse transcriptase, during their life cycle. Retroviruses include,but are not limited to, the RNA viruses of the Retroviridae family, andalso the DNA viruses of the Hepadnavirus and Caulimovirus families.Retroviruses cause a variety of disease states in man, animals andplants. Some of the more important retroviruses from a pathologicalstandpoint include human immunodeficiency viruses (HIV-1 and HIV-2),which cause acquired immune deficiency syndrome (AIDS) in man, hepatitisB virus, which causes hepatitis and hepatic carcinomas in man, humanT-cell lymphotrophic viruses I, II, IV and V, which cause human acutecell leukemia, and bovine and feline leukemia viruses which causeleukemia in domestic animals.

Proteases are enzymes which cleave proteins at specific peptide bonds.Many biological functions are controlled or mediated by proteases andtheir complementary protease inhibitors. For example, the protease renincleaves the peptide angiotensinogen to produce the peptide angiotensinI. Angiotensin I is further cleaved by the protease angiotensinconverting enzyme (ACE) to form the hypotensive peptide angiotensin II.Inhibitors of renin and ACE are known to reduce high blood pressure invivo. An inhibitor of a retroviral protease should provide a therapeuticagent for diseases caused by the retrovirus.

The genomes of retroviruses encode a protease that is responsible forthe proteolytic processing of one or more polyprotein precursors such asthe pol and gag gene products. See Wellink, Arch. Virol. 98 1 (1988).Retroviral proteases most commonly process the gag precursor into coreproteins, and also process the pol precursor into reverse transciptaseand retroviral protease. In addition, retroviral proteases are sequencespecific. See Pearl, Nature 328 482 (1987).

The correct processing of the precursor polyproteins by the retroviralprotease is necessary for the assembly of infectious virions. It hasbeen shown that in vitro mutagenesis that produces protease-defectivevirus leads to the production of immature core forms which lackinfectivity. See Crawford, J. Virol. 53 899 (1985); Katoh, et al.,Virology 145 280 (1985). Therefore, retroviral protease inhibitionprovides an attractive target for antiviral therapy. See Mitsuya, Nature325 775 (1987).

Current treatments for viral diseases usually involve administration ofcompounds that inhibit viral DNA synthesis. Current treatments for AIDS(Dagani, Chem. Eng. News, November 23, 1987 pp. 41-49) involveadministration of compounds such as 2',3'-dideoxycytidine,2',3'-dideoxyinosine, trisodium phosphonoformate, ammonium21-tungsto-9-antimoniate,1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide,3'-azido-3'-deoxythymidine, and adriamycin that inhibit viral DNAsynthesis; compounds such as AL-721 and polymannoacetate which mayprevent HIV from penetrating the host cell; and compounds which treatthe opportunistic infections caused by the immunosuppression resultingfrom HIV infection. None of the current AIDS treatments have proven tobe totally effective in treating and/or reversing the disease. Inaddition, many of the compounds currently used to treat AIDS causeadverse side effects including low platelet count, renal toxicity andbone marrow cytopenia.

DISCLOSURE OF THE INVENTION

In accordance with the present invention, there are retroviral proteaseinhibiting compounds of the formula:

    A--X--B                                                    (I)

or a pharmaceutically acceptable salt, prodrug or ester thereof.

X is ##STR1## wherein R₁ and R_(1') are independently selected fromhydrogen, loweralkyl, alkoxyalkyl, thioalkoxyalkyl and alkoxyalkoxyalkylor R₁ and R_(1') and the oxygen atoms to which they are bonded takentogether are --O--C(O)--O-- or --O--C(S)--O-- and R₂ and R₃ areindependently --((R₀)_(d) --R₅) wherein at each occurrence R₀ isindependently selected from --(CH₂ R₄)-- and loweralkenylene wherein ateach occurrence d is independently selected from 0 and 1, at eachoccurrence R₄ is independently selected from --S--, --O--, --NH--,--N(loweralkyl)--, --S(O)--, --S(O)₂ -- and --CH₂ -- and at eachoccurrence R₅ and R₅, are independently selected from

(i) loweralkyl,

(ii) aryl,

(iii) thioalkoxyalkyl

(iv) (aryl)alkyl,

(v) cycloalkyl,

(vi) cycloalkylalkyl,

(vii) hydroxyalkyl,

(viii) alkoxyalkyl,

(ix) aryloxyalkyl,

(x) haloalkyl,

(xi) carboxyalkyl,

(xii) alkoxycarbonylalkyl,

(xiii) aminoalkyl,

(xiv) (N-protected) aminoalkyl,

(xv) alkylaminoalkyl,

(xvi) ((N-protected)(alkyl)amino)alkyl,

(xvii) dialkylaminoalkyl,

(xviii) guanidinoalkyl,

(xix) loweralkenyl,

(xx) heterocyclic,

(xxi) (heterocyclic)alkyl,

(xxii) hydrogen,

(xxiii) arylthioalkyl,

(xxiv) arylsulfonylalkyl,

(xxv) (heterocyclic)thioalkyl,

(xxvi) (heterocyclic)sulfonylalkyl,

(xxvii) (heterocyclic)oxyalkyl,

(xxviii arylalkoxyalkyl,

(xxix) arylthioalkoxyalkyl,

(xxx) arylalkylsulfonylalkyl,

(xxxi) (heterocyclic)alkoxyalkyl,

(xxxii) (heterocyclic)thioalkoxyalkyl,

(xxxiii (heterocyclic)alkylsulfonylalkyl,

(xxxiv) cycloalkyloxyalkyl,

(xxxv) cycloalkylthioalkyl,

(xxxvi) cycloalkylsulfonylalkyl,

(xxxvii cycloalkylalkoxyalkyl,

xxxviii cycloalkylthioalkoxyalkyl,

(xxxix) cycloalkylalkylsulfonylalkyl,

(xl) aminocarbonyl,

(xli) alkylaminocarbonyl,

(xlii) dialkylaminocarbonyl,

(xliii) aroylalkyl,

(xliv) (heterocyclic)carbonylalkyl,

(xlv) polyhydroxyalkyl,

(xlvi) aminocarbonylalkyl,

(xlvii) alkylaminocarbonylalkyl and

(xlviii dialkylaminocarbonylalkyl.

A and B are independently selected from

(1) Z--W-- wherein at each occurrence W is absent or represents apeptide chain containing 1-3 amino acids wherein and at each occurrenceZ is R₆ --(C(R_(5*))(R₅))_(e) --(C(T))_(f) --(C(R_(5*))(R₅))_(g)--(U)_(i) --(C(R_(5*))(R₅))_(j) --C(T)_(f) -- or R₆ --C(T)_(ff)--(U)_(ii) --CH(R_(5a))-CH(R_(5b))--(U)_(iii) --C(T)_(ff) --. At eachoccurrence R₆ --(C(R_(5*))(R₅))_(e) --(C(T))_(f) --(C(R_(5*))(R₅))_(g)--(U)_(i) --(C(R_(5*))(R₅))_(j) --C(T)_(f) -- or R₆ --C(T)_(ff)--(U)_(ii) --CH (R_(5a))--CH(R_(5b))--(U)_(iii) --C(T)_(ff) -- is bondedto the amino terminus of the peptide chain, at each occurrence T isindependently selected from O and S, at each occurrence R₅ and R_(5*)are independently defined as above or R₅, R_(5*) and the carbon atom towhich they are bonded or R_(5a), R_(5b) and the carbon atoms to whichthey are bonded taken together form a carbocyclic ring of from 3 to 8carbon atoms which can be optionally substituted with a loweralkyl groupor when e, g or j is 2 or more, R₅ and R_(5*) on adjacent carbon atomswhen taken together form a carbocyclic ring of from 3 to 8 carbon atomswhich can be optionally substituted with a loweralkyl group, at eachoccurrence U is independently selected from O, S and --N(R₅)-- whereinR₅ is independently defined as above, at each occurrence e isindependently selected from 0, 1, 2 and 3, at each occurrence f and ffare independently selected from 0 and 1, at each occurrence g isindependently selected from 0, 1, 2 and 3, at each occurrence i, ii andiii are independently selected from 0 and 1, at each occurrence j isindependently selected from 0, 1, 2 and 3, and at each occurrence R₆ isindependently selected from

(a) R₇ --(R₉)_(k) -- wherein at each occurrence R₉ is independentlyselected from N(R₇), O and S and at each occurrence k is independentlyselected from 0 and 1,

(b) (R₇)₂ N--O--,

(c) R₇ S(O)₂ N(R₅)-- and

(d) R₁₇₀ R₁₇₁ CH═CH-- wherein at each occurrence R₁₇₁ is absent, O, S,NH or --N(alkyl)-- and at each occurrence R₁₇₀ is aryl or heterocyclicand wherein at each occurrence R₅ is independently defined as above andat each occurrence R₇ is independently selected from:

(i) hydrogen,

(ii) loweralkyl,

(iii) cycloalkyl,

(iv) aryl,

(v) arylalkyl,

(vi) (aryl)alkoxyalkyl,

(vii) aminoalkyl,

(viii) N-protected-aminoalkyl,

(ix) alkylaminoalkyl,

(x) (N-protected)(alkyl)aminoalkyl,

(xi) dialkylaminoalkyl,

(xii) carboxyalkoxyalkyl,

(xiii) (alkoxycarbonyl)alkoxyalkyl,

(xiv) carboxyalkyl,

(xv) alkoxycarbonylalkyl,

(xvi) (amino)carboxyalkyl,

(xvii) ((N-protected)amino)carboxyalkyl,

(xviii) (alkylamino)carboxyalkyl,

(xix) ((N-protected)alkylamino)carboxyalkyl,

(xx) (dialkylamino)carboxyalkyl,

(xxi) (amino)alkoxycarbonylalkyl,

(xxii) ((N-protected)amino)alkoxycarbonylalkyl,

(xxiii) (alkylamino)alkoxycarbonylalkyl,

(xxiv) ((N-protected)alkylamino)alkoxycarbonylalkyl,

(xxv) (dialkylamino)alkoxycarbonylalkyl,

(xxvi) aminocycloalkyl,

(xxvii) alkoxyalkyl,

(xxviii) (polyalkoxy)alkyl,

(xxix) heterocyclic,

(xxx) (heterocyclic)alkyl,

(xxxi) (hydroxyamino)alkyl,

(xxxii) (alkoxyamino)alkyl,

(xxxiii) N-protecting group,

(xxxiv) cycloalkylalkyl,

(xxxv) loweralkenyl,

(xxxvi) hydroxyalkyl,

(xxxvii) dihydroxyalkyl,

(xxxviii) (alkoxy)(alkyl)aminoalkyl,

(xxxix) alkylaminocycloalkyl,

(ix) dialkylaminocycloalkyl,

(lxi) polyhydroxyalkyl,

(lxii) aryloxyalkyl,

(lxiii) arylthioalkyl,

(lxiv) arylsulfonylalkyl,

(lxv) (heterocyclic)thioalkyl,

(lxvi) (heterocyclic)sulfonylalkyl,

(lxvii) (heterocyclic)oxyalkyl,

(lxviii) arylalkoxyalkyl,

(lxix) arylthioalkoxyalkyl,

(lxx) arylalkylsulfonylalkyl,

(lxxi) (heterocyclic)alkoxyalkyl,

(lxxii) (heterocyclic)thioalkoxyalkyl,

(lxxiii) (heterocyclic)alkylsulfonyalkyl,

(lxxiv) cycloalkyloxyalkyl,

(lxxv) cycloalkylthioalkyl,

(lxxvi) cycloalkylsulfonylalkyl,

(lxxvii) cycloalkylalkoxyalkyl,

(lxxviii) cycloalkylthioalkoxyalkyl,

(lxxix) cycloalkylalkylsufonylalkyl,

(lxxx) aroylalkyl,

(lxxxi) (heterocyclic)carbonylalkyl,

(lxxxii) (aryl)aminoalkyl,

(lxxxiii) (aryl)(alkyl)aminoalkyl,

(lxxxiv) (arylalkyl)aminoalkyl,

(lxxxv) (arylalkyl)(alkyl)aminoalkyl,

(lxxxvi) (heterocyclic)aminoalkyl,

(lxxxvii) (heterocyclic)(alkyl)aminoalkyl,

(lxxxviii ((heterocyclic)alkyl)aminoalkyl,

(lxxxix) ((heterocyclic)alkyl)alkylaminoalkyl

(xc) (alkoxyalkyl)aminoalkyl,

(xci) thioalkoxyalkyl,

(xcii) mercaptoalkyl,

(xciii) aminocarbonylalkyl,

(xciv) alkylaminocarbonylalkyl and

(xcv) dialkylaminocarbonylalkyl; and

(2) Z'--W'-- wherein at each occurrence W' is absent or represents apeptide chain containing 1-3 amino acids and wherein at each occurrenceZ' is R₆ --(C(R_(5*))(R₅))_(e) --(S(O))_(m) --(C(R_(5*))(R₅))_(g)--(U)_(i) --(C(R_(5*))(R₅))_(j) --C(T)_(i) -- or R₆ --(S(O))_(m)--(U)_(ii) --CH(R_(5a))--CH(R_(5b))--(U)_(iii) --C (T)_(i) -- wherein R₆--(C(R_(5*))(R₅))_(e) --(S(O))_(m) --(C(R_(5*))(R₅))_(g) --(U)_(i)--(C(R_(5*))(R₅))_(j) --C(T)_(i) -- or R₆ --(S(O))_(m) --(U)_(ii)--CH(R_(5a))--CH(R_(5b))--(U)_(iii) --C(T)_(ff) -- is bonded to theamino terminus of the peptide chain. At each occurrence T isindependently selected from O and S, at each occurrence R₅ and R_(5*)are independently defined as above or R₅, R_(5*) and the carbon atom towhich they are bonded or R_(5a), R_(5b) and the carbon atoms to whichthey are bonded taken together form a carbocyclic ring of from 3 to 8carbon atoms which can be optionally substituted with a loweralkyl groupor when e, g or j is 2 or more, R₅ and R_(5*) on adjacent carbon atomswhen taken together form a carbocyclic ring of from 3 to 8 carbon atomswhich can be optionally substituted with a loweralkyl group, at eachoccurrence U is independently selected from O, S and --N(R₅)-- whereinR₅ is independently defined as above, at each occurrence e isindependently selected from 0, 1, 2 and 3, at each occurrence m isindependently selected from 1 and 2, at each occurrence g isindependently selected from 0, 1, 2 and 3, at each occurrence i, ii andiii are independently selected from 0 and 1, at each occurrence j isindependently selected from 0, 1, 2 and 3, and at each occurrence R₆ isindependently defined as above.

Preferred compounds of the invention are compounds of the formulaA--X--B wherein X is ##STR2## and wherein A is R₆--C(O)--NH--CH(R₅)--C(O)-- wherein R₅ and R₆ are defined as above and Bis --C(O)--R₆ wherein R₆ is independently defined as above; or apharmaceutically acceptable salt, prodrug or ester thereof.

Preferred compounds of the invention also are compounds of the formula Iwherein X is ##STR3## wherein R₁, R₂ and R₃ are defined as above.

More preferred compounds of the invention are compounds of the formula:

    A--X--B

wherein X is ##STR4## wherein R₁ is hydrogen, loweralkyl or alkoxyalkyland R₂ and R₃ are independently R₅ wherein at each occurrence R₅ isindependently defined as above.

A and B are independently selected from Z-- wherein at each occurrence Zis R₆ --(CH(R₅))_(e) --(C(T))_(f) --(CH(R₅))_(g) --(U)_(i)--(CH(R₅))_(j) --C(T)_(f) --. At each occurrence T is independentlyselected from O and S, at each occurrence R₅ is independently defined asabove, at each occurrence U is independently selected from O, S and--N(R₅)-- wherein R₅ is independently defined as above, at eachoccurrence e is independently selected from 0, 1, 2 and 3, at eachoccurrence f is independently selected from 0 and 1, at each occurrenceg is independently selected from 0, 1, 2 and 3, at each occurrence i isindependently selected from 0 and 1, at each occurrence j isindependently selected from 0, 1, 2 and 3, and at each occurrence R₆ isindependently selected from R₇ (R₇ --(R₉)_(k) -- wherein at eachoccurrence R₉ is independently selected from N(R₇), O and S and at eachoccurrence k is independently selected from 0 and 1 and at eachoccurrence R₇ is independently defined as above.

Most preferred compounds of the invention are compounds of the formula:##STR5## wherein R₁ is hydrogen, R₂ and R₃ are independently selectedfrom (aryl)alkyl, A is R₆ --C(O)--NH--CH(R_(5a))--C(O)-- wherein R_(5a)is loweralkyl and R₆ is R₇ --R₉ -- wherein R₇ is heterocyclic or(heterocyclic)alkyl and R₉ is --N(R_(7a))--, S or O wherein R_(7a) ishydrogen or loweralkyl and B is --C(O)--R_(6') wherein R_(6') is R_(7')--R_(9') -- wherein R_(7') is heterocyclic or (heterocyclic)alkyl andR_(9') is --N(R_(7a'))--, S or O wherein R_(7a') is hydrogen orloweralkyl;

or a pharmaceutically acceptable salt, prodrug or ester thereof.

Most preferred compounds of the invention also are compounds of theformula: ##STR6## wherein R₁ is hydrogen, R₂ and R₃ are independentlyselected from (aryl)alkyl, A is --C(O)--R_(6') wherein R_(6') is R_(7')--R_(9') -- wherein R_(7') is heterocyclic or (heterocyclic)alkyl andR_(9') is --N(R_(7a'))--, S or O wherein R_(7a') is hydrogen orloweralkyl and B is R₆ --C(O)--NH--CH(R_(5a))--C(O)-- wherein R_(5a) isloweralkyl and R₆ is R₇ --R₉ -- wherein R₇ is heterocyclic or(heterocyclic)alkyl and R₉ is --N(R_(7a))--, S or O wherein R_(7a) ishydrogen or loweralkyl; or a pharmaceutically acceptable salt, prodrugor ester thereof.

Most preferred compounds of the invention also are compounds of theformula: ##STR7## wherein R₁ is hydrogen,

R₂ and R₃ are independently selected from (aryl)alkyl, and A and B areindependently is --C(O)--R₆ wherein R₆ is R₇ --R₉ wherein at eachoccurrence R₇ is independently selected from heterocyclic and(heterocyclic)alkyl and at each occurrence R₉ is independently selectedfrom --N(R_(7a))--, S and O wherein R_(7a) is hydrogen or loweralkyl;

or a pharmaceutically acceptable salt, prodrug or ester thereof.

The term "a peptide chain of 1-3 amino acids" as used herein includes--(N(R₁₀)--CH(R₅)--C(O))_(n) -- wherein at each occurrence R₅ isindependently defined as above, at each occurrence n is independentlyselected from 1, 2 and 3, and at each occurrence R₁₀ is independentlyselected from hydrogen and loweralkyl, or R₅ and R₁₀ taken together is--(CH₂)_(p) -- wherein p is 3-5.

The compounds of the invention comprise asymmetrically substitutedcenters. Such centers can be racemic or asymmetric. Racemic mixtures,mixtures of diastereomers, as well as single diastereomers of thecompounds of the invention are included in the present invention. Theterms "S" and "R" configuration are as defined by the IUPAC 1974Recommendations for Section E, Fundamental Stereochemistry, Pure Appl.Chem. (1976) 45, 13-30.

The terms "Ile", "Val" and "Thr" as used herein refer to isoleucine,valine and threonine, respectively. In general, the amino acidabbreviations used herein follow the IUPAC-IUB Joint Commission onBiochemical Nomenclature for amino acids and peptides (Eur. J. Biochem.1984, 158, 9-31).

The term "N-protecting group" or "N-protected" as used herein refers tothose groups intended to protect the N-terminus of an amino acid orpeptide or to protect an amino group against undersirable reactionsduring synthetic procedures. Commonly used N-protecting groups aredisclosed in Greene, "Protective Groups In Organic Synthesis," (JohnWiley & Sons, New York (1981)), which is hereby incorporated byreference. N-protecting groups comprise carbamates, amides, N-alkylderivatives, amino acetal derivatives, N-benzyl derivatives, iminederivatives, enamine derivatives and N-heteroatom derivatives. PreferredN-protecting groups are formyl, acetyl, benzoyl, pivaloyl,t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc),benzyloxycarbonyl (Cbz) and the like. N-protecting groups also refer toan L- or D-aminoacyl residue, which is derived from an L- or D- aminoacid.

The term "O-protecting group" as used herein refers to a substituentwhich protects hydroxyl groups against undesirable reactions duringsynthetic procedures such as those O-protecting groups disclosed inGreene, "Protective Groups In Organic Synthesis," (John Wiley & Sons,New York (1981)). O-protecting groups comprise substituted methylethers, for example, methoxymethyl, benzyloxymethyl,2-methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, t-butyl, benzyland triphenylmethyl; tetrahydropyranyl ethers; substituted ethyl ethers,for example, 2,2,2-trichloroethyl; silyl ethers, for example,trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl; andesters prepared by reacting the hydroxyl group with a carboxylic acid,for example, acetate, propionate, benzoate and the like.

The term "loweralkyl" as used herein refers to straight or branchedchain alkyl radicals containing from 1 to 6 carbon atoms including, butnot limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,sec-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl,2,2-dimethylpropyl, n-hexyl and the like.

The term "alkylene" as used herein refers to a straight or branchedchain carbon diradical containing from 1 to 6 carbon atoms including,but not limited to, --CH₂ --, --CH₂ CH₂ --, --CH(CH₃)CH₂ --, --CH₂ CH₂CH₂ -- and the like.

The term "loweralkenyl" as used herein refers to a loweralkyl radicalwhich contains at least one carbon-carbon double bond including, but notlimited to, propenyl, butenyl and the like. Alkenyl groups can beunsubstituted or substituted with one or more substituents independentlyselected from loweralkyl, haloalkyl, cycloalkyl, aryl, heterocyclic,alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo,mercapto, nitro, carboxaldehyde, carboxy, carboalkoxy and carboxamide.

The term "loweralkenylene" as used herein refers to a straight orbranched chain carbon diradical containing from 2 to 6 carbon atomswhich contains a carbon-carbon double bond including, but not limitedto, --CH═CH--, --C(CH₃)═CH--, --CH₂ CH═CH--, --CH₂ --CH═CH--CH₂ -- andthe like.

The term "aryl" as used herein refers to a C6 monocyclic aromatic ringsystem or a C₉ or C₁₀ bicyclic carbocyclic ring system having one ormore aromatic rings including, but not limited to, phenyl, naphthyl,tetrahydronaphthyl, indanyl, indenyl and the like. Aryl groups can beunsubstituted or substituted with one, two or three substituentsindependently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy,alkoxycarbonyl, alkanoyl, hydroxy, halo, mercapto, nitro, amino,alkylamino, dialkylamino, carboxaldehyde, carboxy, carboxamide,arylalkyl, arylalkoxy, (heterocyclic)alkyl, (heterocyclic)alkoxy,aminoalkyl, aminoalkoxy, alkylaminoalkyl, alkylaminoalkoxy,dialkylaminoalkyl, dialkylaminoalkoxy, (alkoxyalkyl)aminoalkyl,(alkoxyalkyl)aminoalkoxy, di-(alkoxyalkyl)aminoalkyl,di-(alkoxyalkyl)aminoalkoxy, (alkoxyalkyl)(alkyl)aminoalkyl,(alkoxyalkyl)(alkyl)aminoalkoxy, hydroxyalkyl, hydroxyalkoxy,carboxyalkyl, carboxyalkoxy, alkoxyalkyl, thioalkoxyalkyl,polyalkoxyalkyl and dialkoxyalkyl. In addition, substituted aryl groupsinclude tetrafluorophenyl and pentafluorophenyl.

The term "arylalkyl" as used herein refers to an aryl group appended toa loweralkyl radical including, but not limited to, benzyl,4-hydroxybenzyl, 1-naphthylmethyl and the like.

The term "aminoalkyl" as used herein refers to --NH₂ appended to aloweralkyl radical.

The term "cyanoalkyl" as used herein refers to --CN appended to aloweralkyl radical.

The term "hydroxyalkyl" as used herein refers to --OH appended to aloweralkyl radical.

The term "dihydroxyalkyl" as used herein refers to a loweralkyl radicaldisubstituted with --OH groups.

The term "polyhydroxyalkyl" as used herein refers to a loweralkylradical substituted with more than two --OH groups.

The term "mercaptoalkyl" as used herein refers to a loweralkyl radicalto which is appended a mercapto (--SH) group.

The term "hydroxyaminoalkyl" as used herein refers to a hydroxyaminogroup (--NHOH) appended to a loweralkyl radical.

The term "alkoxyaminoalkyl" as used herein refers to --NHR₂₀ (whereinR₂₀ is an alkoxy group) appended to a loweralkyl radical.

The term "(alkoxy)(alkyl)aminoalkyl" as used herein refers to(R₂₁)(R₂₂)N-- wherein R₂₁ is alkoxy and R₂₂ is loweralkyl appended to aloweralkyl radical.

The term "alkylamino" as used herein refers to a loweralkyl radicalappended to an NH radical.

The term "hydroxyalkylamino" as used herein refers to a hydroxyalkylgroup appended to an NH radical.

The term "dihydroxyalkylamino" as used herein refers to a dihydroxyalkylgroup appended to an NH radical.

The term "(hydroxyamino)alkylamino" as used herein refers to --NHR₂₃wherein R₂₃ is a hydroxyaminoalkyl group.

The term "(alkoxyamino)alkylamino" as used herein refers to --NHR₂₄wherein R₂₄ is an alkoxyaminoalkyl group.

The term "((hydroxyamino)alkyl)(alkyl)amino" as used herein refers to--NR₂₅ R₂₆ wherein R₂₅ is a hydroxyaminoalkyl group and R₂₆ is aloweralkyl group.

The term "((alkoxyamino)alkyl)(alkyl)amino" as used herein refers to--NR₂₇ R₂₈ wherein R₂₇ is an alkoxyaminoalkyl group and R₂₈ is aloweralkyl group.

The term "(N-protected)aminoalkylamino" as used herein refers to anN-protected amino group which is appended to a loweralkyl group which inturn is appended to an --NH radical.

The term "cycloalkyl" as used herein refers to an aliphatic ring having3 to 7 carbon atoms including, but not limited to, cyclopropyl,cyclopentyl, cyclohexyl and the like. Cycloalkyl groups can beunsubstituted or substituted with one, two or three substituentsindependently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy,amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro,carboxaldehyde, carboxy, carboalkoxy and carboxamide.

The term "cycloalkylalkyl" as used herein refers to a cycloalkyl groupappended to a loweralkyl radical, including but not limited tocyclohexylmethyl.

The term "alkylaminocycloalkyl" as used herein refers to an alkylaminogroup appended to a cycloalkyl radical.

The term "dialkylaminocycloalkyl" as used herein refers to adialkylamino group appended to a cycloalkyl radical.

The terms "alkoxy" and "thioalkoxy" as used herein refer to R₂₉ O-- andR₂₉ S--, respectively, wherein R₂₉ is a loweralkyl group or benzyl.

The term "haloalkoxy" as used herein refers to R₂₉ 'O-- wherein R₂₉ ' isa haloalkyl group

The term "(hydroxyamino)alkoxy" as used herein refers to R₃₀ O-- whereinR₃₀ is a hydroxyaminoalkyl group.

The term "(alkoxyamino)alkoxy" as used herein refers to R₃₁ O-- whereinR₃₁ is an alkoxyaminoalkyl group.

The term "alkoxyalkyl" as used herein refers to an alkoxy group appendedto a loweralkyl radical.

The term "thioalkoxyalkyl" as used herein refers to a thioalkoxy groupappended to a loweralkyl radical.

The term "alkoxyalkoxyalkyl" as used herein refers to an alkoxy groupappended to an alkoxy group which is in turn appended to a loweralkylradical including, but not limited to, methoxyethoxymethyl and the like.

The term "guanidinoalkyl" as used herein refers to a guanidino group(--NHC(═NH)NH₂) appended to a loweralkyl radical.

The term "alkenyloxy" as used herein refers to R₃₂ O-- wherein R₃₂ is aloweralkenyl group.

The term "hydroxyalkoxy" as used herein refers to --OH appended to analkoxy radical.

The term "dihydroxyalkoxy" as used herein refers to an alkoxy radicalwhich is disubstituted-with --OH groups.

The term "arylalkoxy" as used herein refers R₃₃ O-- wherein R₃₃ is aarylalkyl group as defined above.

The term "(heterocyclic)alkoxy" as used herein refers to R₃₄ O-- whereinR₃₄ is a (heterocyclic)alkyl group.

The term "aryloxyalkyl" as used herein refers to a R₃₅ O-- groupappended to a loweralkyl radical, wherein R₃₅ is an aryl group.

The term "dialkylamino" as used herein refers to --NR₃₆ R₃₇ wherein R₃₆and R₃₇ are independently selected from loweralkyl groups.

The term "(hydroxyalkyl)(alkyl)amino" as used herein refers to --NR₃₈R₃₉ wherein R₃₈ is hydroxyalkyl and R₃₉ is loweralkyl.

The term "N-protected aminoalkyl" as used herein refers to --NHR₄₀appended to a loweralkyl group, wherein R₄₀ is an N-protecting group.

The term "alkylaminoalkyl" as used herein refers to NHR₄₁ appended to aloweralkyl radical, wherein R₄₁ is a loweralkyl group.

The term "(N-protected)(alkyl)aminoalkyl" as used herein refers to--NR₄₂ R₄₃, which is appended to a loweralkyl radical, wherein R₄₂ andR₄₃ are as defined above.

The term "dialkylaminoalkyl" as used herein refers to --NR₄₄ R₄₅ whichis appended to a loweralkyl radical wherein R₄₄ and R₄₅ areindependently selected from loweralkyl.

The term "azidoalkyl" as used herein refers to a --N₃ group appended toa loweralkyl radical.

The term "carboxyalkyl" as used herein refers to a carboxylic acid group(--COOH) appended to a loweralkyl radical.

The term "alkoxycarbonylalkyl" as used herein refers to a R₄₆ C(O)--group appended to a loweralkyl radical, wherein R₄₆ is an alkoxy group.

The term "carboxyalkoxyalkyl" as used herein refers to a carboxylic acidgroup (--COOH) appended to an alkoxy group which is appended to aloweralkyl radical.

The term "alkoxycarbonylalkoxyalkyl" as used herein refers to analkoxycarbonyl group (R₄₇ C(O)-- wherein R₄₇ is an alkoxy group)appended to an alkoxy group which is appended to a loweralkyl radical.

The term "(amino)carboxyalkyl" as used herein refers to a loweralkylradical to which is appended a carboxylic acid group (--COOH) and anamino group (--NH₂).

The term "((N-protected)amino)carboxyalkyl" as used herein refers to aloweralkyl radical to which is appended a carboxylic acid group (--COOH)and --NHR₄₈ wherein R₄₈ is an N-protecting group.

The term "(alkylamino)carboxyalkyl" as used herein refers to aloweralkyl radical to which is appended a carboxylic acid group (--COOH)and an alkylamino group.

The term "((N-protected)alkylamino)carboxyalkyl" as used herein refersto a loweralkyl radical to which is appended a carboxylic acid group(--COOH) and an --NR₄₈ R₄₉ wherein R₄₈ is as defined above and R₄₉ is aloweralkyl group.

The term "(dialkylamino)carboxyalkyl" as used herein refers to aloweralkyl radical to which is appended a carboxylic acid group (--COOH)and --NR₄₉ R₄₉ wherein R₄₉ is as defined above.

The term "(amino)alkoxycarbonylalkyl" as used herein refers to aloweralkyl radical to which is appended an alkoxycarbonyl group asdefined above and an amino group (--NH₂ ).

The term "((N-protected)amino)alkoxycarbonylalkyl" as used herein refersto a loweralkyl radical to which is appended an alkoxycarbonyl group asdefined above and --NHR₅₀ wherein R₅₀ is an N-protecting group.

The term "(alkylamino)alkoxycarbonylalkyl" as used herein refers to aloweralkyl radical to which is appended an alkoxycarbonyl group asdefined above and an alkylamino group as defined above.

The term "((N-protected)alkylamino)alkoxycarbonylalkyl" as used hereinrefers to a loweralkyl radical to which is appended an alkoxycarbonylgroup as defined above and --NR₅₁ R₅₂ wherein R is an N-protecting groupand R₅₂ is a loweralkyl group.

The term "(dialkylamino)alkoxycarbonylalkyl" as used herein refers to aloweralkyl radical to which is appended an alkoxycarbonyl group asdefined above and --NR₅₃ R₅₄ wherein R₅₃ and R₅₄ are independentlyselected from loweralkyl.

The term "carboxyalkylamino" as used herein refers to --NHR₅₅ wherein Ris a carboxyalkyl group.

The term "alkoxycarbonylalkylamino" as used herein refers to --NHR₅₆wherein R is an alkoxycarbonylakyl group.

The term "(amino)carboxyalkylamino" as used herein refers to --NHR₅₇wherein R₅₇ is an (amino)carboxyalkyl group.

The term "((N-protected)amino)carboxyalkylamino" as used herein refersto --NHR₅₈ wherein R₅₈ is an [(N-protected)amino]carboxyalkyl group.

The term"(alkylamino)carboxyalkylamino" as used herein refers to --NHR₅₉wherein R₅₉ is an (alkylamino)carboxyalkyl group.

The term "((N-protected)alkylamino)carboxyalkylamino" as used hereinrefers to --NHR₆₀ wherein R₆₀ is an((N-protected)alkylamino)carboxyalkyl group.

The term "(dialkylamino)carboxyalkylamino" as used herein refers to--NHR₆₁ wherein R₆₁ is a (dialkylamino) carboxyalkyl group.

The term "(amino)alkoxycarbonylalkylamino" as used herein refers to--NHR₆₂ wherein R₆₂ is an (amino)alkoxycarbonylalkyl group.

The term "((N-protected)amino)alkoxycarbonylalkylamino" as used hereinrefers to --NHR₆₃ wherein R₆₃ is an((N-protected)amino)alkoxycarbonylalkyl group.

The term "(alkylamino)alkoxycarbonylalkylamino" as used herein refers to--NHR₆₄ wherein R₆₄ is an (alkylamino)alkoxycarbonylalkyl group.

The term "((N-protected)alkylamino)alkoxycarbonylalkylamino" as usedherein refers to --NHR₆₅ wherein R₆₅ is an((N-protected)alkylamino)alkoxycarbonylalkyl group.

The term "(dialkylamino)alkoxycarbonylalkylamino" as used herein refersto --NHR₆₆ wherein R₆₆ is a (dialkylamino)alkoxycarbonylalkyl group.

The term "aminocycloalkyl" as used herein refers to an NH₂ appended to acycloalkyl radical.

The term "((alkoxy)alkoxy)alkyl" as used herein refers to an alkoxygroup appended to an alkoxy group which is appended to a loweralkylradical.

The term "polyalkoxyalkyl" as used herein refers to a polyalkoxy residueappended to a loweralkyl radical.

The term "polyalkoxy" as used herein refers to --OR₆₇ wherein R₆₇ is astraight or branched chain containing 1-5, C_(n') --O--C_(n") linkageswherein n' and n" are independently selected from 1 to 3, including butnot limited to methoxyethoxymethoxy, methoxymethoxy and the like.

The term "(arylalkyl)amino" as used herein refers to R₆₈ NH-- whereinR₆₈ is an arylalkyl group as defined above.

The term "(arylalkyl)(alkyl)amino" as used herein refers to R₆₉ R₇₀ N--wherein R₆₉ is an arylalkyl group as defined above and R₇₀ is aloweralkyl group.

The term "(heterocyclic)alkylamino" as used herein refers to R₇₁ NH--wherein R₇₁ is a (heterocyclic)alkyl group.

The term "((heterocyclic)alkyl)(alkyl)amino" as used herein refers toR₇₂ R₇₃ N-- wherein R₇₂ is a (heterocyclic)alkyl group and R₇₃ is aloweralkyl group.

The term "dialkylaminoalkyl(alkyl)amino" as used herein refers to --NR₇₈R₇₉ wherein R₇₈ is a dialkylamino residue appended to a loweralkylresidue and R₇₉ is a loweralkyl residue.

The term "alkylaminoalkylamino" as used herein refers to --NHR₈₀ whereinR₈₀ is an alkylaminoalkyl group as previously defined.

The term "dialkylaminoalkylamino" as used herein refers to --NHR₈₁wherein R₈₁ is a dialkylaminoalkyl group as previously defined.

The term "aminoalkylamino" as used herein refers to --NHR₈₂ wherein R₈₂is an aminoalkyl residue.

The term "(dihydroxyalkyl)(alkyl)amino" as used herein refers to aloweralkyl group which is disubstituted with --OH radicals, appended toan amino group, which amino group also has appended another loweralkylgroup, including but not limited toN-(2,3-dihydroxypropyl)-N-(methyl)amine.

The term "di-(hydroxyalkyl)amino" as used herein refers to --NR₈₃ R₈₄wherein R₈₃ and R₈₄ are hydroxyalkyl residues.

The term "alkoxyalkyl(alkyl)amino" as used herein refers to --NR₈₅ R₈₆wherein R₈₅ is an alkoxyalkyl group and R₈₆ is a loweralkyl group.

The term "di-(alkoxyalkyl)amino" as used herein refers to --NR₈₇ R₈₈wherein R₈₇ and R₈₈ are alkoxyalkyl groups.

The term "di-(polyalkoxyalkyl)amino" as used herein refers to --NR₈₉ R₉₀wherein R₈₉ and R₉₀ are polyalkoxy residues appended to loweralkylresidues.

The term "((polyalkoxy)alkyl))(alkyl)amino" as used herein refers to--NR₉₁ R₉₂ wherein R₉₁ is a polyalkoxy residue appended to a loweralkylresidue and R₉₂ is a loweralkyl residue.

The term "halo" or "halogen" as used herein refers to --Cl, --Br, --I or--F.

The term "haloalkyl" as used herein refers to a loweralkyl radical inwhich one or more of the hydrogen atoms are replaced by halogenincluding, but not limited to, chloromethyl, trifluoromethyl,1-chloro-2-fluoroethyl and the like.

The term "thioalkoxyalkyl" as used herein refers to a thioalkoxy groupappended to a loweralkyl radical.

The term "alkylsulfonyl" as used herein refers to R₉₃ SO₂ -- wherein R₉₃is loweralkyl group.

The term "arylthioalkyl" as used herein refers to R₉₄ --S--R₉₅ --wherein R₉₄ is an aryl group and R₉₅ is an alkylene group.

The term "arylsulfonylalkyl" as used herein refers to R₉₆ --S(O)₂ --R₉₇-- wherein R₉₆ is any aryl group and R₉₇ is an alkylene group.

The term "(heterocyclic) oxyalkyl" as used herein refers to R₉₈ --O--R₉₉-- wherein R₉₈ is an aryl group and R₉₉ is an alkylene group.

The term "(heterocyclic)thioalkyl" as used herein refers to R₁₀₀--S--R₁₀₁ -- wherein R₁₀₀ is an aryl group and R₁₀₁ is an alkylenegroup.

The term "(heterocyclic) sulfonylalkyl" as used herein refers to R₁₀₂--S(O)₂ --R₁₀₃ -- wherein R₁₀₂ is an aryl group and R₁₀₃ is an alkylenegroup.

The "arylalkoxyalkyl" as used herein refers to R₁₀₄ --O--R₁₀₅ -- whereinR₁₀₄ is an arylalkyl group and R₁₀₅ is an alkylene group.

The "arylthioalkoxyalkyl" as used herein refers to R₁₀₆ --S--R₁₀₇ --wherein R₁₀₆ is an arylalkyl group and R₁₀₇ is an alkylene group.

The "arylalkylsulfonylalkyl" as used herein refers to R₁₀₈ --S(O)₂--R₁₀₉ -- wherein R₁₀₈ is an arylalkyl group and R₁₀₉ is an alkylenegroup.

The term "(heterocyclic)alkoxyalkyl" as used herein refers to R₁₁₀--O--R₁₁₁ -- wherein R₁₁₀ is a (heterocyclic)alkyl group and R₁₁₁ is analkylene group.

The term "(heterocyclic) thioalkoxyalkyl" as used herein refers to R₁₁₂--S--R₁₁₃ -- wherein R₁₁₂ is a (heterocyclic)alkyl group and R₁₁₃ is analkylene group.

The term "(heterocyclic)alkylsulfonylalkyl" as used herein refers toR₁₁₄ --S(O)₂ --R₁₁₅ -- wherein R₁₁₄ is a (heterocyclic)alkyl group andR₁₁₅ is an alkylene group.

The term "cycloalkyloxyalkyl" as used herein refers to R₁₁₆ --O--R₁₁₇ --wherein R₁₁₆ is a cycloalkyl group and R₁₁₇ is an alkylene group.

The term "cycloalkylthioalkyl" as used herein refers to R₁₁₈ --S--R₁₁₉-- wherein R₁₁₈ is a cycloalkyl group and R₁₁₉ is an alkylene group.

The term "cycloalkylsulfonylalkyl" as used herein refers to R₁₂₀ --S(O)₂--R₁₂₁ -- wherein R₁₂₀ is a cycloalkyl group and R₁₂₁ is an alkylenegroup.

The term "cycloalkylalkoxyalkyl" as used herein refers to R₁₂₂ --O--R₁₂₃-- wherein R₁₂₂ is a cycloalkylalkyl group and R₁₂₃ is an alkylenegroup.

The term "cycloalkylthioalkoxyalkyl" as used herein refers to R₁₂₄--S--R₁₂₅ -- wherein R₁₂₄ is a cycloalkylalkyl group and R₁₂₅ is analkylene group.

The term "cycloalkylalkylsulfonylalkyl" as used herein refers to R₁₂₆--S(O)₂ --R₁₂₇ -- wherein R₁₂₆ is a cycloalkylalkyl group and R₁₂₇ is analkylene group.

The term "alkanoyl" as used herein refers to R_(k) --C(O)-- whereinR_(k) is a loweralkyl group.

The term "aminocarbonyl" as used herein refers to --C(O)NH₂.

The term "aminocarbonylalkyl" as used herein refers to an aminocarbonylgroup appended to a loweralkyl radical.

The term "alkylaminocarbonyl" as used herein refers to --C(O)NHR₁₂₈wherein R₁₂₈ is loweralkyl.

The term "alkylaminocarbonylalkyl" as used herein refers to analkylaminocarbonyl group appended to a loweralkyl radical.

The term "dialkylaminocarbonyl" as used herein refers to --C(O)NR₁₂₉R₁₃₀ wherein R₁₂₉ and R₁₃₀ are independently selected from loweralkyl.

The term "dialkylaminocarbonylalkyl" as used herein refers to adialkylaminocarbonyl group appended to a loweralkyl group.

The term "aroylalkyl" as used herein refers to R₁₃₁ --C(O)--R₁₃₂ --wherein R₁₃₁ is an aryl group and R₁₃₂ is an alkylene group.

The term "(heterocyclic) carbonylalkyl" as used herein refers to R₁₃₃--C(O)--R₁₃₄ -- wherein R₁₃₃ is a heterocyclic group and R₁₃₄ is analkylene group.

The term "arylamino" as used herein refers to R₁₃₅ NH-- wherein R₁₃₅ isan aryl group.

The term "(heterocyclic)amino" as used herein refers to R₁₃₆ NH--wherein R₁₃₆ is a heterocyclic group.

The term "aminoalkoxy" as used herein refers to an alkoxy radical towhich is appended an amino (--NH₂) group.

The term "alkylaminoalkoxy" as used herein refers to an alkoxy radicalto which is appended an alkylamino group.

The term "dialkylaminoalkoxy" as used herein refers to an alkoxy radicalto which is appended a dialkylamino group.

The term "(alkoxyalkyl)aminoalkyl" refers to a loweralkyl radical towhich is appended an (alkoxyalkyl)amino group.

The term "(alkoxyalkyl)aminoalkoxy" as used herein refers to an alkoxyradical to which is appended an (alkoxyalkyl)amino group.

The term "(alkoxyalkyl)(alkyl)aminoalkyl" refers to a loweralkyl radicalto which is appended an (alkoxyalkyl)(alkyl)amino group.

The term "(alkoxyalkyl)(alkyl)aminoalkoxy" as used herein refers to analkoxy radical to which is appended an (alkoxyalkyl)(alkyl)amino group.

The term "di-(alkoxyalkyl)aminoalkyl" refers to a loweralkyl radical towhich is appended an di(alkoxyalkyl)amino group.

The term "d-(alkoxyalkyl)aminoalkoxy" as used herein refers to an alkoxyradical to which is appended an di(alkoxyalkyl)amino group.

The term "carboxyalkoxy" as used herein refers to an alkoxy radical towhich is appended a carboxy (--COOH) group.

The term "aminocarbonylalkyl" as used herein refers to a loweralkylradical to which is appended an aminocarbonyl (NH₂ C(O)--) group.

The term "alkylaminocarbonylalkyl" as used herein refers to a loweralkylradical to which is appended an alkylaminocarbonyl group.

The term "dialkylaminocarbonylalkyl" as used herein refers to aloweralkyl radical to which is appended an dialkylaminocarbonyl group.

At each occurrence, the term "heterocyclic ring" or "heterocyclic" asused herein independently refers to a 3- or 4-membered ring containing aheteroatom selected from oxygen, nitrogen and sulfur; or a 5- or6-membered ring containing one, two or three heteroatoms independentlyselected from N, O and S. The 5-membered ring has 0-2 double bonds andthe 6membered ring has 0-3 double bonds. The nitrogen heteroatoms can beoptionally quaternized or N-oxidized. The sulfur heteroatoms can beoptionally S-oxidized. The term "heterocyclic also includes bicyclicgroups in which any of the above heterocyclic lings is fused to abenzene ring or a cyclohexane ring or another heterocyclic ring.Heterocyclics include: pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl,pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl,pyridyl, piperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl,oxazolyl, oxazolinyl, oxazolidinyl, isoxazolyl, isoxazolinyl,isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl,isothiazolidinyl, indolyl, quinolinyl, tetrahydroquinolyl,isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl,benzofuranyl, furyl, dihydrofuranyl, tetrahydrofuranyl, pyranyl,dihydropyranyl, tetrahydropyranyl, dioxanyl, dioxolanyl, thienyl andbenzothienyl.

Heterocyclics also include: ##STR8##

Heterocyclics can be unsubstituted or monosubstituted or disubstitutedwith substituents independently selected from hydroxy, halo, oxo (═O),alkylimino (R*N═ wherein R* is a loweralkyl group), amino,(N-protected)amino, alkylamino, (N-protected)alkylamino, dialkylamino,alkoxy, polyalkoxy, haloalkyl, cycloalkyl, aryl, arylalkyl, --COOH,--SO₃ H and loweralkyl. In addition, nitrogen containing heterocyclescan be N-protected.

The term "(heterocyclic)alkyl" as used herein refers to a heterocyclicgroup appended to a loweralkyl radical, including but not limited toimidazolylmethyl and thiazolylmethyl.

The term "heterocyclic carbonyloxy" as used herein refers to R₁₃₇C(O)O-- wherein R₁₃₇ is a heterocyclic group.

The term "heterocyclic carbonylamino" as used herein refers to R₁₃₈C(O)NH-- wherein R₁₃₈ is a heterocyclic group.

The term "(aryl)aminoalkyl" as used herein refers to a loweralkylradical to which is appended R₃₀₀ NH-- wherein R₃₀₀ is an aryl group.

The term "(aryl)(alkyl)aminoalkyl" as used herein refers to a loweralkylradical to which is appended (R₃₀₀)(R₃₀₁)N-- wherein R₃₀₀ is an arylgroup and R₃₀₁ is a loweralkyl group.

The term "(arylalkyl)aminoalkyl" as used herein refers to a loweralkylradical to which is appended R₃₀₂ NH-- wherein R₃₀₂ is an arylalkylgroup.

The term "(arylalkyl)(alkyl)aminoalkyl" as used herein refers to aloweralkyl radical to which is appended (R₃₀₃)(R₃₀₄)N-- wherein R₃₀₃ isan arylalkyl group and R₃₀₄ is a loweralkyl group.

The term "(heterocyclic)aminoalkyl" as used herein refers to aloweralkyl radical to which is appended R₃₀₅ NH-- wherein R₃₀₅ is aheterocyclic group.

The term "(heterocyclic)(alkyl)aminoalkyl" as used herein refers to aloweralkyl radical to which is appended (R₃₀₆)(R₃₀₇)N-- wherein R₃₀₆ isa heterocyclic group and R₃₀₇ is a loweralkyl group.

The term "((heterocyclic)alkyl)aminoalkyl" as used herein refers to aloweralkyl radical to which is appended R₃₀₈ NH-- wherein R₃₀₈ is a(heterocyclic)alkyl group.

The term "((heterocyclic)alkyl)(alkyl)aminoalkyl" as used herein refersto a loweralkyl radical to which is appended (R₃₀₉)(R₃₁₀)N-- whereinR₃₀₉ is a (heterocyclic)alkylalkyl group and R₃₁₀ is a loweralkyl group.

The term "(alkoxyalkyl)aminoalkyl" as used herein refers to a loweralkylradical to which is appended R₃₁₁ NH-- wherein R₃₁₁ is an alkoxyalkylgroup.

When any variable (i.e., R₁, R₂, R₃, etc.) occurs more than one time inany substituent or in a compound of formula I, its definition on eachoccurrence is independent of its definition at every other occurrence.Also, combinations of substituents and/or variables are permissible onlyif such combinations result in stable compounds.

Preferred compounds of the invention are selected from the groupconsisting of:

(2S,3S,5S)-2-(N-(N-((2-Pyridinyl)methoxycarbonyl)valinyl)amino)-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane;

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((3-pyridinyl)-methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane;

(2S,3S,5S)-2-(N-((3-Pyridinyl)-methoxycarbonyl)amino-5-(N-(N-((N-Methyl-N-((6-methyl-2-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-1,6-diphenyl-3-hydroxyhexane;

(2S,3S,5S)-2-(N-(N-((N-Methyl-N-((2-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane;

(2S,3S,5S)-5-(N-(N-((2-Pyridinyl)methoxycarbonyl)valinyl)amino)-2-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane;

(2S,3S,5S)-5-(N-(N-((N-methyl-N-((2-pyridinyl)methyl)amino)carbonyl)isoleucinyl)amino)-2-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

(2S,3S,5S)-2,5-Di{N-(3-pyridylmethyl)oxy-carbonyl)amino}-3-hydroxy-1,6-diphenylhexane;

(2S,3S-5S)-2-(N-(N-((N-Methyl-N-((6-methyl-2-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-5-(N-((3-pyridinyl)-methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane;and

(2S,3S,5S)-2-(N-[(pyridin-3-yl)methoxycarbonyl]amino)-5-(N-[(6-methylpyridin-2-yl)methoxycarbonylvalyllamino)-1,6-diphenyl-3-hydroxyhexane;

or a pharmaceutically acceptable salt, ester or prodrug thereof.

Compounds useful as intermediates for the preparation of the compound offormula I include the compound of the formula: ##STR9## wherein P₁ andP₂ are independently selected from hydrogen and an N-protecting group;R₁ ' is hydrogen, loweralkyl, alkoxyalkyl or an O-protecting group; andR₂ and R₃ are --((R₀)_(d) --R₅)_(d) --R₅) wherein at each occurrence R₀is independently selected from --(CH₂ R₄)-- and loweralkenylene whereinat each occurrence d is independently selected from 0 and 1, at eachoccurrence R₄ is independently selected from --S--, --O--, --NH--,--N(loweralkyl)--, --S(O)--, --S(O)₂ -- and --CH₂ -- and at eachoccurrence R₅ is independently selected from (i) loweralkyl, (ii) aryl,(iii) thioalkoxyalkyl, (iv)(aryl) alkyl, (v) cycloalkyl, (vi)cycloalkylalkyl, (vii) hydroxyalkyl, (viii) alkoxyalkyl, (ix)aryloxyalkyl, (x) haloalkyl, (xi) caboxyalkyl, (xii)alkoxycarbonylalkyl, (xiii) aminoalkyl, (xiv) (N-protected) aminoalkyl,(xv) alkylaminoalkyl, (xvi) ((N-protected)(alkyl)amino)alkyl, (xvii)dialkylaminoalkyl, (xviii) guanidinoalkyl, (xix) loweralkenyl, (xx)heterocyclic, (xxi) (heterocyclic)alkyl, (xxii) hydrogen, (xxiii)arylthioalkyl, (xxiv) arylsulfonylalkyl, (xxv) (heterocyclic)thioalkyl,(xxvi) (heterocyclic)sulfonylalkyl, (xxvii) (heterocyclic)oxyalkyl,(xxviii) arylalkoxyalkyl, (xxix) arylthioalkoxyalkyl, (xxx)arylalkylsulfonylalkyl, (xxxi) (heterocyclic)alkoxyalkyl, (xxxii)(heterocyclic)thioalkoxyalkyl, (xxxiii)(heterocyclic)alkylsulfonylalkyl, (xxxiv) cycloalkyloxyalkyl, (xxxv)cycloalkylthioalkyl, (xxxvi) cycloalkylsulfonylalkyl, (xxxvii)cycloalkylalkoxyalkyl, (xxxviii) cycloalkylthioalkoxyalkyl, (xxxix)cycloalkylalkylsulfonylalkyl, (xl) aminocarbonyl, (xli)alkylaminocarbonyl, (xlii) dialkylaminocarbonyl, (xliii) aroylalkyl,(xliv) (heterocyclic)carbonylalkyl, (xlv) polyhydroxyalkyl, (xlvi)aminocarbonylalkyl, (xlvii) alkylaminocarbonylalkyl and (xlviii)dialkylaminocarbonylalkyl; or a salt or ester thereof.

The compounds of the invention can be prepared as shown in Schemes 1-5.The syntheses of carboxylic acids (A--OH and B--OH) and p-nitrophenylesters (A--OPNP and B--OPNP) are described in the Examples. The processshown in Scheme 1 discloses the pinacol coupling of a protectedaminoaldehyde (I) to give (II) and (III). Diols (II) and (III) areindependently deoxygenated by initial reaction with α-acetoxyisobutyrylbromide and lithium bromide followed by reduction of the intermediatebromoacetate with tri-n-butyltin hydride to provide (IV) and (V),respectively. Basic hydrolysis of (IV) and (V) leads to (VI) and (VII),respectively.

The process described in Scheme 2 discloses the dimesylation andpyrolysis of (II) to provide (IX). Basic hydrolysis of (II) and (IX)provides (VIII) and (X), respectively. Treatment of (II) withα-acetoxyisobutyryl bromide in the absence of lithium bromide leads to(XI). Alternately, monomesylation of (II) to give (XIII) followed bypyrolysis in acetonitrile provides (XIV). Basic hydrolysis of either(XI) or (XIV) leads to (XII).

Another alternative process for converting (II) to the epimerizedproduct (XII) is illustrated in Scheme 2A. Monoacetylation of (II)provides (XXX). Mesylation of (XXX), followed by heating provides (XI).Hydrolysis of (XI) gives (XII).

The process described in Scheme 3 discloses the aminolysis of (IV) togive the alcohol (XV). Mesylation of (XV) to give (XVI) followed bypyrolysis provides : (E)-alkene (XVIII). Basic hydrolysis gives thediamine (XVIII).

The process described in Scheme 4 discloses the sequential addition ofdiisobutylaluminum hydride and vinylmagnesium bromide to (XIX) to givethe mixture of allylic alcohols (XX). Mesylation of (XX) followed bydisplacement with R₃ MgBr/catalytic cuprous cyanide provides (E)-alkene(XXI). Epoxidation of (XXI) gives (XXII) which is opened with lithiumazide to provide (XXIII). Reduction of the azido group in (XXIII) togive (XXIV) followed by acidic deprotection of (XXIV) leads to diamine(XXV).

The process described in Scheme 5 discloses the assemblage of HIVprotease inhibitors from intermediate (XXVI), which representsstructures (VI, (X'═--CH(OH)CH₂ --)), (VII, (X'═--CH(OH)CH₂ --)), (VIII,(X'═--CH(OH)CH(OH)--)), (X, (X'═--CH(OH)CH(OH)--)), (XII,(X'═--CH(OH)CH(OH)--)), (XVIII, (X'═--CH═CH--)), or (XXV,(X'═--CH(OH)--)). (X' can also be --CH₂ CH₂ --, --CH(OH)CF₂ --,--C(O)CF₂ -- or --CH₂ CH(OH)CH₂ --).

The transformation of (XXVI) to (XXVII) can be achieved via an activeester such as a p-nitrophenyl ester of a carboxylic or sulfonic acid, orthrough direct coupling of the acid with (XXVI) in the presence of acoupling reagent. Alternately, protected α-aminoacids (W) can be coupledto (XXVI) to provide (XXVIII). Deprotection to give (XXIX), followed bycoupling with Z--OH or activated derivatives thereof provides (XXVII).Alternatively, (XXVI) can be coupled with Z--W--OH or activatedderivatives thereof to provide (XXVII).

Coupling reagents known in the art which can be used include, but arenot limited to, dicyclohexylcarbodiimide (DCC),3-ethyl-3'-(dimethylamino)propylcarbodiimide (EDC),bis(2-oxo-3-oxazolidinyl)-phosphinic chloride (BOP--Cl),diphenylphosphoryl azide (DPPA) and the like.

In addition to the use of the carboxylic acids or sulfonic acids forcoupling with amines, acid halides and other activated esters are usefulfor coupling with amines. Acid halide derivatives include the acidchloride. Activated ester derivatives include activated esters commonlyused by those skilled in the art for activating carboxylic acid groupsfor coupling with an amine to form an amide bond or for coupling with analcohol for forming an ester bond including, but not limited to, formicand acetic acid derived anhydrides, anhydrides derived fromalkoxycarbonyl halides such as isobutyloxycarbonylchloride and the like,N-hydroxysuccinimide derived seters, N-hydroxyphthalimide derivedesters, N-hydroxybenzotriazole derived esters,N-hydroxy-5-norbornene-2,3-dicarboxamide derived esters,2,4,5-trichlorophenol derived esters and the like.

Scheme 6 illustrates the preparation of a particular substituent A whichis N-(N'-2-pyridylmethyl-N'-methyl-aminocarbonyl)-L-valine (XXXV).2-Picolinaldehyde (XXXI) is converted to 2-(N-methyl)aminomethylpyridine(XXXII) by treatment with methylamine, followed by hydrogenation.Reaction of (XXXII) with the methyl or benzyl ester ofN-phenoxycarbonyl-L-valine ((XXXIII) provides (XXXIV). Hydrolysis (R═Me)or hydrogenation (R═benzyl) of (XXXIV) provides (XXXV).

Scheme 7 illustrates the preparation of the compounds of the inventionwherein A and B are not identical. Starting with diamine (XXXVII) as arepresentative substituent X, monoacylation of the diamine with thep-nitrophenyl ester or p-nitrophenyl carbonate of A--OH provides amixture of (XXXVIII) and (XXXIX). This mixture can be separated bysilica gel chromatography. Acylation of (XXXVIII) with the p-nitrophenylester or p-nitrophenyl carbonate of B--OH provides (XL). Similarly,acylation of (XXXIX) with the p-nitrophenyl ester or p-nitrophenylcarbonate of B--OH provides (XLI).

Scheme 8 illustrates the preparation of compounds of the inventionhaving substituent X derived from (XLIV) or (XLV). Reaction of aldehyde(XLII) with aminoester (XLIII) provides (XLIV). N-Oxidation of (XLIV)provides (XLV). Deprotection of (XLV) and coupling with the appropriatesubstituents A and B provides (XLVII). Alternatively, deprotection of(XLIV), followed by coupling with A and B and N-oxidation, provides(XLVII). ##STR10## a, VCl₃.(THF)₃, Zn, CH₂ Cl₂ ; b, LiBr,α-acetoxyisobutyryl bromide, CH₃ CN; c, (n--Bu)₃ SnH, AIBN, THF; d,Ba(OH)₂.8H₂ O, H₂ O, dioxane. ##STR11## a (OH)₂.8H₂ O, H₂ O, dioxane CH₃Cl₂ ; c, DMF, 120° C.; d, α-acetoxyisobutyryl bromide, CH₃ CN; e, MsCl,Et₃ N, DMAP, CH₂ Cl₂ ; f, CH₃ CN, reflux. ##STR12## a, NH₄ OH, H₂ O, CH₃OH; b, MsCl, Et₃ N, DMAP, CH₂ Cl₂ ; c, DMF, reflux; d, Ba(OH)₂.8H₂ O, H₂O, dioxane. ##STR13## a, DIBAL, PhCH₃ ; vinylmagnesium bromide, THF; b,MsCl, EtN(i--Pr)₂, CH₂ Cl₂ ; c, R₃ MgBr, cat. CuCN, THF; d, MCPBA, CH₂Cl₂ ; e, LiN₃, NH₄ Cl, DMF, H₂ O; f, ammonium formate, Pd/C, CH₃ OH; g,HCl, dioxane; NaOH. ##STR14## a, A--OPNP/B--OPNP orA--OH/B--OH+carbodiimide; b, Cbz--W--OPNP or Cbz--W--OH+carbodiimide; c,H₂, Pd/C, CH₃ OH; d, Z--OH or Z--OPNP. ##STR15## a, A--OPNP, THF or CH₂Cl₂, b, silica gel chromatography; c, B--OPNP, THF or CH₂ Cl₂. ##STR16##a, NaOAc, NaCNBH₃, i--PrOH; b, dimethyldioxirane, acetone.

The following examples will serve to further illustrate preparation ofthe novel compounds of the invention.

EXAMPLE 1 A. Cbz-L-phenylalaninal

A solution of 24.5 ml of anhydrous dimethyl sulfoxide in ml of anhydrousdichloromethane was cooled under N₂ atmosphere to -60° C. and treatedover a period of 15 min with ml of a 2M solution of oxalyl chloride indichloromethane in order that the internal temperature remained below-50° C. After addition, the solution was stirred at -60° C. for 15 minand treated over a period of 20 rain with a solution of 50 g (0.175 mol)of Cbz-L-phenylalaninol in 200 ml of dichloromethane. The resultingsolution was stirred at -60° C. for 1 h, then treated over a period of15 min with 97 ml of triethylamine in order that the internaltemperature remained below -50° C. After addition the solution wasstirred at -60° C. for 15 min, then, with the cooling bath in place, wastreated rapidly (over a period of 1 min) with a solution of 163 g ofcitric acid in 550 ml of water. The resulting slurry was stirredvigorously for 10 min, allowed to warm, diluted to 1 liter with water,and separated. The organic layer was washed with 700 ml of waterfollowed by a mixture of 550 ml of water and 150 ml of saturated aqueousNaHCO₃, dried over MgSO₄, and concentrated in vacuo at 20° C. to givethe crude desired compound as a light yellow solid.

B. (2S,3R,4R,5S)-2,5-Bis-(N-Cbz-amino)-3,4-dihydroxy-1,6-diphenylhexaneand (2S,3S,4S,5S)-2,5-Bis-(N-Cbz-amino)-3,4-dihydroxy-1,6-diphenylhexane

A suspension of 78.5 g of VCl₃.(tetrahydrofuran)₃ and 16 g of zinc dustin 400 ml of dry dichloromethane was stirred under N₂ atmosphere for 1 hat 25° C. A solution of 0.175 mol of Cbz-L-phenylalaninal in 200 ml ofdichloromethane was then added in one portion, and the resulting mixturewas stirred at ambient temperature under N₂ atmosphere for 16 h. Theresulting mixture was added to 500 ml of 1M aqueous HCl, diluted with500 ml of hot chloroform, and shaked vigorously for 2 min. The layerswere separated, and the organic layer was washed with 1M aqueous HCl andseparated. Filtration of the organic phase provided the crude desiredproduct as a solid residue. The residue was slurried in 1.25 liters ofacetone, treated with 5 ml of concentrated H₂ SO₄, and stirred for 16 hat ambient temperature. The resulting mixture was filtered, and theresidue (residue A) was washed with 50 ml of acetone. The combinedfiltrate was concentrated to a volume of 250 ml, diluted with 1000 ml ofdichloromethane, washed three times with water and once with saturatedbrine, dried over MgSO₄, and concentrated to give a viscous oil. The oilwas taken up in 1000 ml of 1M HCl in methanol (prepared from 71 ml ofacetyl chloride and 1000 ml of methanol) and stirred at ambienttemperature for 2 h. The resulting precipitate was filtered, washed withmethanol, and air-dried on the filter to provide 26.7 g of the desiredcompound as a white solid. The filtrate was concentrated and filtered togive a second crop (8.3 g) of(2S,3R,4R,5S)-2,5-bis-(N-Cbz-amino)-3,4-dihydroxy-1,6-diphenylhexane. ¹H NMR (d₆ -DMSO) δ 2.59 (dd, J=13, 5 Hz, 2H), 2.74 (dd, J=13, 9 Hz, 2H),3.26 (br, 2H), 4.19 (m, 2H), 4.54 (m, 2H), 4.92 (m, 4H), 6.82 (d, J=9Hz, 2H), 7.0-7.35 (m, 20H). Mass spectrum: (M+H)⁺ =569.

Residue A (above, 2.65 g) was suspended in 75 ml of tetrahydrofuran and75 ml of 1M aqueous HCl and heated at reflux for 24 h. Afterconcentration of the resulting solution in vacuo, the residue was takenup in 10% methanol in, chloroform, washed two times with water, driedover Na₂ SO₄, and concentrated in vacuo to provide(2S,3S,4S,5S)-2,5-bis-(N-Cbz-amino)-3,4-dihydroxy-1,6-diphenylhexane asa white solid. ¹ H NMR (d₆ -DMSO) δ 2.64 (m, 2H), 3.04 (m, 2H), 3.49 (m,2H), 3.78 (m, 2H), 4.70 (d, J=7 Hz, 2H), 4.93 (AA', 4H), 7.1-7.4 (m,20H). Mass spectrum: (M+H)⁺ =569.

C.(2S,3R,4S,5S)-3-Acetoxy-2,5-bis-(N-Cbz-amino)-3-bromo-1,6-diphenylhexane

A suspension of 25 g (44 mmol) of(2S,3R,4R,5S)-2,5-bis-(N-Cbz-amino)-3,4-dihydroxy-1,6-diphenylhexane in500 ml of 2:1 dichloromethane/hexane was treated with 23 g ofα-acetoxyisobutyryl bromide. The resulting mixture was stirred atambient temperature until the reaction clarified, washed with two 200 mlportions of saturated aqueous NaHCO₃, dried over MgSO₄, and concentratedin vacuo to give 30.8 g of the crude desired compound. A portion waspurified by silica gel chromatography using 9:1 dichloromethane:ethylacetate to provide the pure desired compound as a white solid. ¹ H NMR(CDCl₃) δ 2.21 (s, 3H), 2.62 (dd, J=13, 11 Hz, 1H), 2.75 (d, J=7 Hz,2H), 2.95 (br d, J=15 Hz, 1H), 4.03 (br t, J=10 Hz, 1h), 4.40 (br d,J=10 Hz, 1H), 4.6-5.0 (m, 6H), 5.12 (br d, J=13 Hz, 1H), 5.33 (br d,J=11 Hz, 1H), 7.0-7.4 (m, 10H). Mass spectrum: (M+NH₄)⁺ =690, 692.

D. (2S,3S,5S)-3-Acetoxy-2,5-bis-[N-Cbz-amino)-1,6-diphenylhexane

A solution of 30.8 g (44 mmol) of the crude resultant compound ofExample 1C in 600 ml of tetrahydrofuran was treated with 17.8 ml (66mmol) of tri-n-butyltin hydride and 1.45 g (8.8 mmol) of2,2'-azobis-[2-methylpropionitrile]. The resulting solution was heatedat reflux under N₂ atmosphere for 1.5 h. After being allowed to cool,the solution was concentrated in vacuo, and the residue was taken upinto acetonitrile and washed with four portions of hexane. Theacetonitrile layer was dried over MgSO₄, filtered, and concentrated invacuo to provide 32 g of the crude desired compound. Mass spectrum:(M+NH₄)⁺ =612.

E. (2S,3S,5S)-2,5-Diamino-1,6-diphenyl-3-hydroxyhexane

A suspension of 32 g of the crude resultant compound of Example 1D and55.5 g (176 mmol) of barium hydroxide octahydrate in 400 ml of1,4-dioxane and 400 ml of water was heated at reflux for 4 h. Theresulting mixture was filtered, and the residue was rinsed with dioxane.The combined filtrates were concentrated to a volume of approximately200 ml and extracted with four 400 ml portions of chloroform. Thecombined organic layers were dried over Na₂ SO₄, filtered, andconcentrated in vacuo. The residue was purified by silica gelchromatography using first 2% isopropylamine in chloroform and then 2%isopropylamine/2% methanol in chloroform to provide 10.1 g (81%) of thepure desired compound as a white solid. ¹ H NMR (CDCl₃) δ 1.54 (dt,J=14, 10 Hz, 1H), 1.67 (dr, J=14, 3 Hz, 1H), 2.50 (dd, J=13, 8 Hz, 1H),2.58 (dd, J=13, 8 Hz, 1H), 2.8 (m, 2H), 2.91 (dd, J=13, 5 Hz, 1H), 3.10(m, 1H), 3.72 (ddd, J=11, 3, 2 Hz, 1H), 7.1-7.4 (m, 10H). Mass spectrum:(M+H)⁺ =285.

EXAMPLE 2 A. α-Isocyanato-valine Methyl Ester

A suspension of L-valine methyl ester hydrochloride (49 g, 0.29 mol) intoluene (700 ml) was heated to 100° C. and phosgene gas was bubbled intothe reaction mixture. After approximately 6 h, the mixture becamehomogeneous. The bubbling of phosgene was continued for 10 more min,then the solution was cooled with the bubbling of N₂ gas. The solventwas then evaporated and the residue chased with toluene two times.Evaporation of solvent gave 40.8 g (89%) of the crude desired compound.

B. N-[(2-Pyridinyl)methoxycarbonyl)-valine Methyl Ester

A solution of 0.78 g (5.0 mmol) of the resultant compound of Example 2Aand 0.55 ml (5.7 mmol) of pyridine-2-methanol in 30 mL of toluene washeated at reflux under N₂ atmosphere for 4 h. The solvent was removed invacuo, and the residue was purified by silica gel chromatography usingmethanol in chloroform to give 0.72 g (54%) of the desired compound asan oil. ¹ H NMR (CDCl₃) δ 0.91 (d, J=7 Hz, 3H), 0.98 (d, J=7 Hz, 3H),2.19 (m, 1H), 3.75 (s, 3H), 4.32 (dd, J=9, 5 Hz, 1H), 5.24 (s, 2H), 5.39(br d, 1H), 7.23 (ddd, J=8, 4, 1 Hz, 1H), 7.37 (d, J=8 Hz, 1H), 7.70(td, J=8, 2 Hz, 1H), 8.60 (br d, 1H). Mass spectrum: (M+H)⁺ =267.

C. N-((2-Pyridinyl)methoxycarbonyl)-valine

Using the procedure of Example 3E but replacing the resultant compoundof Example 3D with the resultant compound of Example 2B provided thedesired compound.

D. N-((2-Pyridinyl)methoxycarbonyl)-valine p-Nitrophenyl Ester

Using the procedure of Example 3F but replacing the resultant compoundof Example 3E with the resultant compound of Example 2C provided thedesired compound.

E.(2S,3S,5S)-2,5-Bis-(N-(N-((2-pyridinyl)methoxycarbonyl)-valinyl)-amino)-1,6-diphenyl-3-hydroxyhexane

A solution of 0.13 g (0.46 mmol) of the resultant compound of Example 1Ein 2 ml of dry dimethylformamide was treated with 0.5 g of the resultantcompound of Example 2D. After being stirred at ambient temperature for16 h, the solution was treated with saturated aqueous NaHCO₃, extractedwith 5% methanol in chloroform, dried over Na₂ SO₄, and concentrated invacuo. The residue was purified by silica gel chromatography using agradient of 2%-3%-5% methanol in chloroform to provide 161 mg (45%) ofthe pure desired compound, m.p. 220°-222° C. Mass spectrum: (M+H)⁺ =753.

Anal. Calcd for C₄₂ H₅₂ N₆ O₇.0.5H₂ O: C, 66.21; H, 7.01; N, 11.03.Found: C, 65.92; H, 6.90; N, 10.80.

EXAMPLE 3 A. 2-(N-(t-Butyloxycarbonyl)aminomethyl)pyridine

A solution of 21.2 g (97 mmol) of di-t-butyldicarbonate in 200 ml ofdichloromethane was cooled to 0° C. and treated in portions with 10 ml(97 mmol) of 2-(aminomethyl)pyridine. After being allowed to warm toambient temperature and stirred overnight, the resulting solution wasdiluted with 100 ml of dichloromethane, washed with three 100 mlportions of water, dried over Na₂ SO₄, and concentrated in vacuo toprovide 19.8 g (98%) of the desired compound (R_(f) 0.28, 5% methanol inchloroform). ¹ H NMR (CDCl₃) δ 1.47 (s, 9H), 4.45 (d, J=6 Hz, 2H), 5.56(br, 1H), 7.18 (m, 1H), 7.28 (d, J=8 Hz, 1H), 7.66 (td, J=7, 2 Hz, 1H),8.53 (m, 1H). Mass spectrum: (M+H)⁺ =209.

B. 2-((N-(t-Butyloxycarbonyl)-N-methylamino)methyl)pyridine

A solution of 19.8 g (95 mmol) of the resultant compound 6f Example 3Ain anhydrous tetrahydrofuran was cooled under N₂ atmosphere to 0° C. andtreated with 4.95 g (124 mmol) of sodium hydride (60% dispersion inoil). The solution was stirred for 15 min, treated dropwise with 7.1 ml(114 mmol) of methyl iodide, stirred at ambient temperature for 2 h, andquenched cautiously with water. The resulting mixture was partitionedbetween ether and water, dried over Na₂ SO₄, and concentrated in vacuo.Chromatography on silica gel provided 14.9 g (70%) of the desiredcompound as a colorless oil. ¹ H NMR (CDCl₃) δ 1.43, 1.49 (two s, 9H),2.89, 2.94 (two s, 3H), 4.54, 4.57 (two S, 2H), 7.2 (m, 2H), 7.67 (td,J=8, 2 Hz, 1H), 8.55 (d, J=4 Hz, 1H). Mass spectrum: (M+H)⁺ =223.

C. 2-(N-Methylamino)methyl)pyridine Dihydrochloride

The resultant compound of Example 3B (10 g) was treated with 200 ml of6M aqueous HCl and heated at reflux for 10 min. After being allowed tocool, the solution was concentrated in vacuo. The residue was treatedtwice with 50 ml of dioxane and concentrated in vacuo to provide thecrude desired compound as a light brown solid.

D. N-((N-Methyl-N-((2-pyridinyl)methyl]amino)carbonyl)-valine MethylEster

A mixture of 1.61 g (7.2 mmol) of the resultant compound of Example 3Cand 1.14 g (7.2 mmol) of the resultant compound of Example 2A in 40 mlof dichloromethane was treated with 2 ml (18 mmol) of4-methylmorpholine. After being stirred for 2 h, the solution waspartitioned between dichloromethane and water, dried over Na₂ SO₄, andconcentrated. Chromatography on silica gel using 2% methanol inchloroform provided 1.94 g (96%) of the desired compound (R_(f) 0.32, 5%methanol in chloroform) as a colorless oil. ¹ H NMR (CDCl₃) δ 0.93 (d,J=7 Hz, 3H), 0.97 (d, J=7 Hz, 3H), 2.16 (m, 1H), 3.03 (s, 3H), 3.72 (s,3H), 4.43 (dd, J=8, 5 Hz, 1H), 4.55 (s, 2H), 6.15 (br, 1H), 7.22 (dd,J=8, 6 Hz, 1H), 7.28 (d, J=6 Hz, 1H), 7.69 (br t, 1H), 8.55 (d, J=5 Hz,1H). Mass spectrum: (M+H)⁺ =280.

E. N-((N-Methyl-N-((2-pyridinyl)-methyl)-amino)-carbonyl)-valine

A solution of 4.47 g (16 mmol) of the resultant compound of Example 3Din 65 ml of dioxane was treated with 65 ml of 0.5M aqueous lithiumhydroxide. After being stirred at ambient temperature for 1 h, theresulting solution was concentrated in vacuo to a small volume (ca. 5ml), neutralized to pH 5 with 1M aqueous HCl, and extracted with three100 ml portions of ethyl acetate. The combined organic layers were driedover Na₂ SO₄ and concentrated in vacuo to provide 3.61 g (85%) of thedesired compound as an oil.

F. N-((N-Methyl-N-((2-pyridinyl)-methyl)-amino)-carbonyl)-valinep-Nitrophenyl Ester

A solution of 3.61 g (13.6 mmol) of the resultant compound of Example 3Eand 2,3 g (16 mmol) of p-nitrophenol in 60 ml of anhydroustetrahydrofuran was treated with 3.09 g (15 mmol) of dicyclohexylcarbodiimide and stirred under N₂ atmosphere at ambient temperature for4 h, The resulting mixture was filtered and the residue was rinsed withfresh tetrahydrofuran, The combined filtrates were concentrated in vacuoto provide the crude desired compound as a yellow oil.

G.(2S,3S,5S)-2,5-Bis-(N-(N-((N-methyl-N-((2-pyridinyl)methyl)-amino)-carbonyl)-valinyl)-amino)-1,6-diphenyl-3-hydroxyhexane

A solution of 1.26 g (4.44 mmol) of the resultant compound of Example 1Ein 20 ml of 1:1 tetrahydrofuran:dimethylformamide was treated with 11mmol of the resultant compound of Example 3F. After being stirred atambient temperature under N₂ atmosphere for 16 h, the resulting solutionwas diluted with 600 ml of ethyl acetate, washed with five 200 mlportions of aqueous NaHCO₃, dried over Na₂ SO₄, and concentrated invacuo. Purification of the residue on silica gel using first 2% methanolin chloroform then 5% methanol in chloroform provided 2.95 g (86%) ofthe pure desired compound as a white solid, m.p. 134°-137° C. Massspectrum: (M+H)⁺ =779.

Anal. Calcd for C₄₄ H₅₈ N₈ O₅ 1.5H₂ O: C, 65.57; H, 7.63; N, 13.90.Found: C, 65.74; H, 7.24; N, 13.83.

EXAMPLE 4 A. (2S,3R,4R,5S)-2,5-Diamino-3,4-dihydroxy-1,6-diphenylhexane

Using the procedure of Example 1E with(2S,3R,4R,5S)-2,5-bis-(N-Cbz-amino)-3,4-dihydroxy-1,6-diphenylhexaneprovided the crude desired compound mixed with benzyl alcohol in 92%yield. Purification of a sample was achieved by silica gelchromatography using 2% isopropylamine in chloroform. ¹ H NMR (CDCl₃) δ2.71 (dd, J=13, 9 Hz, 2H), 2.92 (dd, J=13, 5 Hz, 2H), 3.03 (dd, J=9, 5Hz, 2H), 3.68 (s, 2H), 7.15-7.35 (m, 10H). Mass spectrum: (M+H)⁺ =301.

B.(2S,3R,4R,5S)-2,5-Bis-(N-(Cbz-valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane

A mixture of 2.5 g of the crude resultant compound of Example 4A and 6 gof Cbz-valine p-nitrophenyl ester in 80 ml of tetrahydrofuran wasstirred at ambient temperature for 16 h. The resulting mixture wastreated with 20 ml of 3M aqueous NaOH, stirred for 3 h, and concentratedin vacuo to a volume of 20 ml. The mixture was filtered, and the residuewas washed sequentially with aqueous NaOH (until the residue was white),water, and diethyl ether. The residue was then taken up into 10%methanol in chloroform, dried over Na₂ SO₄, and concentrated in vacuo toprovide 2.77 g (75%) of the desired compound, m.p. 231°-32° C. Massspectrum: (M+H)⁺ =767.

Anal. Calcd for C₄₄ H₅₄ N₄ O₈ 0.25H₂ O: C, 68.51; H, 7.12; N, 7.26.Found: C, 68.48; H, 7.11; N, 7.12.

C.(2S,3R,4R,5S)-2,5-Bis-(N-(valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane

A mixture of 2.21 g of the resultant compound of Example 4B and 0.55 gof 10% palladium-on carbon in 150 ml of methanol was shaken under 4atmospheres of hydrogen for 4 h. The resulting mixture was filteredthrough Celite and concentrated in vacuo to provide the desired compound(R_(f) 0.07, 10% methanol in chloroform) as a white solid, m.p.205°-207° C. Mass spectrum: (M+H)⁺ =499.

Anal. Calcd for C₂₈ H₄₂ N₄ O₄.0.75H₂ O: C, 65.66; H, 8.56; N, 10.94.Found: C, 65.47; H, 7.93; N, 10.59.

D.trans-(2S,3R,4R,5S)-2,5-Bis-(N-(N-(trans-3-(3-pyridinyl)-2-propenoyl)-valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane

Using the procedure of Example 6I but replacing the resultant compoundof Example 6H with the resultant compound of Example 4C provided thedesired compound, m.p. >260° C. Mass spectrum: (M+H)⁺ =761.

EXAMPLE 5 A. trans-Ethyl 3-(2-Pyridinyl)acrylate

A solution of 0.43 g (10.7 mmol) of sodium hydride (60% oil dispersion)in anhydrous tetrahydrofuran was cooled under N₂ atmosphere to 0° C. andtreated dropwise with 2.1 ml (10.5 mmol) of triethylphosphenoacetate.After being stirred for 10 min, the solution was treated with 1.0 ml ofpyridine-2-carboxaldehyde, heated at reflux for 2 h, cooled, partitionedbetween ether and aqueous ammonium chloride, washed sequentially withwater and saturated brine, dried over MgSO₄, and concentrated. Silicagel chromatography of the residue using 30% ethyl acetate in hexaneprovided 1.54 g (83%) of the desired compound as an oil. ¹ H NMR (CDCl₃)δ 1.34 (t, J=7 Hz, 3H), 4.28 (q, J=7 Hz, 2H), 6.92 (d, J=15 Hz, 1H),7.27 (ddd, J=8, 5, 2 Hz, 1H), 7.43 (dr, J=8, 1 Hz, 1H), 7.69 (d, J=15Hz, 1H), 7.71 (td, J=8, 2 Hz, 1H), 8.66 (dm, 1H).

B. trans-3-(2-Pyridinyl)acrylic Acid

A solution of 13.6 g (82 mmol) of the resultant compound of Example 5Ain 330 ml of 1,4-dioxane was treated with 330 ml of 0.5M aqueous lithiumhydroxide. The resulting solution was stirred at ambient temperature for2 h, neutralized with 165 ml of 1N aqueous HCl, concentrated in vacuo toa volume of 200 ml, and extracted with five 100 ml portions ofchloroform. The combined organic layers were dried over Na₂ SO₄ andconcentrated in vacuo to give 11.3 g (94%) of the desired compound as awhite solid.

C.(2S,3R,4R,5S)-2,5-Bis-(N-(N-(trans-3-(3-pyridinyl)-2-propenoyl)-valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane

Using the procedure of Example 61 but replacing the resultant compoundof Example 6H with the resultant compound of Example 4C and replacingtrans-3-(3-pyridyl)acrylic acid with trans-3-(2-pyridyl)acrylic acidprovided the desired compound, m.p. 285°-289° C. Mass spectrum: (M+H)⁺=761.

Anal. Calcd for C₄₄ H₅₂ N₆ O₆.0.75H₂ O: 0: C, 68.24; H, 6.96; N, 10.85.Found: C, 68.04; H, 6.92; N, 10.87.

EXAMPLE 6 A. 4-(t-Butyloxycarbonylamino)-3-hydroxy-5-phenyl-1-pentene

A solution of 10.25 g (36.7 mmol) of N-(t-butyloxycarbonyl)phenylalaninemethyl ester in 60 ml of toluene was cooled to -78° C. under inertatmosphere and treated dropwise over a period of 45 min with 35 ml (52.5mmol) of diisobutylaluminum hydride in toluene. The resulting solutionwas stirred for 5 min, treated with 200 ml (200 mmol) of vinylmagnesiumbromide, and allowed to warm to 0° C. for 16 h. The solution wassubsequently quenched cautiously with methanol, treated with aqueousRochelle salts, stirred for a few min, and filtered. The residue wasdigested several times with ethyl acetate and filtered; and the combinedfiltrates were washed with saturated brine, dried over MgSO₄, andconcentrated. Silica gel chromatography using 20% ethyl acetate inhexane gave 5.46 g (54%) of the pure desired compound as a mixture ofdiastereomers.

B. 2-(t-Butyloxycarbonylamino)-1,5-diphenylpent-3-ene

A solution of 15.1 g (54.5 mmol) of the resultant compound of Example 6Aand 38 ml (220 mmol) of diisopropylethylamine in 450 ml of drydichloromethane was cooled under N₂ atmosphere in an acetone/ice bathand treated dropwise with 8.5 ml (110 mmol) of methanesulfonyl chloride.The solution was stirred for 7 min after addition was complete, then wasquenched with 400 ml of 10% citric acid. The bath was removed, and themixture was extracted with 800 ml of ether. The organic layer was washedsequentially with 500 ml of water and 300 ml of saturated brine, driedover MgSO₄, and concentrated in vacuo to give the crude mesylate as anoff-white solid. To a flame-dried 3-neck 1000 mL flask equipped with aninternal low-temperature thermometer was added 1.45 g (16 mmol) ofanhydrous cuprous cyanide. The flask was then charged with 500 ml ofanhydrous tetrahydrofuran. The suspension was cooled under N₂altmosphere in a dry ice/acetone bath. A solution of phenylmagnesiumbromide (55 ml, 165 mmol) in ether (3M) was added via syringe. The bathwas removed, and the resulting beige suspension was warmed with stirringby use of a water bath. As the internal temperature reached -5° C., thesolid began to dissolve, and the solution began to turn darker. By thetime the internal temperature reached -1° C., the solution washomogenous, and was immediately recooled by placement of the flask in adry ice/acetone bath. As the internal temperature reached -65° C.,addition of a solution of the above crude mesylate in 75 ml oftetrahydrofuran was added via cannula. The resulting solution wasstirred at ca. -70° C. for 15 min. The bath was then removed, and thesolution was immediately treated with 100 ml of saturated aqueousammonium chloride followed by 300 ml of ether. As the mixture warmed,100 ml of 1N NH₄ OH was added, and the mixture was shirred under airatmosphere for several hours while the aqueous layer turned dark blue.The mixture was then extracted with 500 ml of ether. The organic layerwas washed with saturated brine and concentrated in vacuo without dryingto give a yellow oil. The combined aqueous layers were extracted with500 ml of additional ether, which was added to the above oil. Theresulting solution was washed with saturated brine, dried over MgSO₄,and concentrated to a yellow oil. The oil was taken up in 100 ml ofdichloromethane, treated with 50 g of silica gel, and concentrated invacuo until the residue was a freely flowing solid. The solid was placedon top of a 60 mm column containing 300 g of silica gel and elutedsequentially with 1200 ml of hexane (to bring out biphenyl formed as aside product) followed by 5000 ml of 5% ethyl acetate in hexane.Combination of the pure fractions gave 11.95 g (65%) of the desiredcompound. ¹ H NMR (CDCl₃, major isomer) δ 1.40 (s, 9H), 2.7-2.9 (m, 2H),3.32 (d, J=7 Hz, 2H), 4.4 (br, 2H), 5.43 (dd, J=15, 6 Hz, 1H), 5.64 (dr,J=15, 7 Hz, 1H), 7.0-7.3 (m, 10H).

C. 2-(t-Butyloxycarbonylamino)-1,5-diphenylpent-3-ene-3,4-oxide

A solution of 11.71 g (34.75 mmol) of the resultant compound of Example6B in 200 ml of dichloromethane was treated with 15 g (174 mmol) ofsolid sodium bicarbonate, cooled to 0° C., and treated with 24 g (69mmol) of m-chloroperbenzoic acid (50%). The resulting suspension wassealed with a septum and stirred in a cold room (5° C.) for three days.The resulting mixture, which contained much precipitate, was decantedinto a 1000 ml flask. The white residue was broken up and washed outwith 400 ml of 10% sodium thiosulfate solution and 300 ml of ether. Thetwo-phase mixture was stirred for 2 hours, and the layers wereseparated. The organic layer was washed sequentially with 200 mlportions of 2M NaOH, water, and saturated brine. The combined aqueouslayers were extracted with 200 ml of ether, which was washedsequentially with 50 ml of water and 50 mL of aqueous brine, combinedwith the original organic phase, dried over MgSO₄, and concentrated invacuo. The resulting oil was taken up in 100 ml of dichloromethane,treated with 50 g of silica gel, and concentrated in vacuo until theresidue was a freely flowing solid. The solid was placed on top of a 60mm column containing 300 g of silica gel and eluted sequentially with1000 ml of 5% ethyl acetate in hexane followed by 3500 ml of 12% ethylacetate in hexane. Concentration of the combined fractions gave 9.36 g(76%) of the desired compound (ca. 4:1 mixture of diastereomers) as anoil which solidified upon standing.

D. 4-Azido-2-(t-butytoxycarbonylamino)-1,5-diphenyl-3-hydroxypentane

A solution of 9.12 g (25.84 mmol) of the resultant compound of Example6C, 7.0 g (140 mmol) of lithium azide, and 1.73 g (32 mmol) of ammoniumchloride in 75 ml of dimethylformamide and 7.5 ml of water was heated inan oil bath at 70° C. for 32 hours. After being allowed to cool, theresulting solution was treated with 1000 ml of 1:1 ether/hexane and 800ml of water. The layers were separated, and the aqueous layer wasextracted with 500 ml of additional 1:1 ether/hexane.. The combinedorganic layers were washed sequentially with 400 ml of water and 200 mlof saturated brine, dried over MgSO₄, and concentrated in vacuo to asolid. The solid was taken up in 100 ml of dichloromethane, treated with50 g of silica gel, and concentrated in vacuo until the residue was afreely flowing solid. The solid was placed on top of a 60 mm columncontaining 300 g of silica gel and eluted sequentially with 1000 ml of10% ethyl acetate in hexane, 1000 ml of 15% ethyl acetate in hexane, and2000 ml of 25% ethyl acetate in hexane. Concentration of the fractionsgave 9.26 g (91%) of the desired compound as a ca. 4:1 mixture ofdiastereomers. ¹ H NMR (CDCl₃, major isomer) δ 1.42 (s, 9H), 2.78 (m,1H), 2.89 (m, 1H), 3.13 (m, 1H) 3.29 (m, 1H), 3.41 (m, 1H), 3.53 (m,1H), 3.80 (m, 1H) 4.06 (m, 1H), 4.83 (m, 1H), 7.2-7.35 (m, 10H). Massspectrum (M+H)⁺ =338.

E. 4-Amino-2-(t-butyloxycarbonylamino)-1,5-diphenyl-3-hydroxypentane

A rapidly stirring suspension of 1.8 g of 10% palladium on carbon in 50ml of methanol was treated under inert atmosphere with 10 g (0.16 mol)of solid ammonium formate. After 10 min, a solution of 8.95 g (22.6mmol) of the resultant compound of Example 6D in 80 ml of methanol wasadded. The resulting mixture was stirred for 2.5 h, filtered throughCelite, and the catalyst was washed with 200 ml of 1:1 methanol: 1Nammonium hydroxide. The combined filtrates were concentrated in vacuo toa volume of 100 ml. The resulting mixture was treated with 1N NaOH andextracted with two portions of chloroform. The combined organic layerswere dried over sodium sulfate and concentrated. The residue waschromatographed on 300 g of silica gel using the following eluents: 500ml of 2% methanol in chloroform, 500 ml of 5% methanol in chloroform,1500 ml of 10% methanol in chloroform, and 1000 ml of 2%isopropylamine/10% methanol in chloroform. Concentration of theappropriate fractions provided 5.85 g (70%) of(2S,3S,4S)-4-amino-2-(t-butyloxycarbonylamino)-1,5-diphenyl-3-hydroxypentane(R_(f) 0.38, 2.5% methanol/2% isopropylamine in chloroform) as a whitesolid, m.p. 134°-135° C. ¹ H NMR (CDCl₃) δ 1.48 (s, 9H), 2.50 (dd, J=13,10 Hz, 1H), 2.8-3.1 (m, 4H), 3.41 (br d, J=7 Hz, 1H), 4.11 (br q, J=8Hz, 1H), 4.83 (br d, J=9 Hz, 1H), 7.15-7.35 (m, 10H). Mass spectrum(M+H)⁺ =370.

Anal. Calcd. for C₂₂ H₃₀ N₂ O₃.0.15H₂ O: C, 70.81; H, 8.18; N, 7.51.Found: C, 70.89; H, 8.15; N, 7.43.

Also isolated in the chromatography was 1.22 g (15%) of(2S,3R,4R)-4-amino-2-(t-butyloxycarbonylamino)-1,5-diphenyl-3-hydroxypentane.

F. (2S,4S)-2,4-Diamino-1,5-diphenyl-3-hydroxypentane

The resultant compound of Example 6E (18 mg, 0.049 mmol) was treatedwith 1 ml of 4M HCl in dioxane, stirred for 0.5 h at ambienttemperature, and concentrated in vacuo. The residue was partitionedbetween chloroform and aqueous NaHCO₃, dried over Na₂ SO₄ andconcentrated to provide the desired compound (R_(f) 0.12, 10% methanolin chloroform) as a white solid, m.p. 106°-107° C. ¹ H NMR (CDCl₃) δ2.51 (dd, J=13, 10 Hz, 1H), 2.67 (dd, J=13, 9 Hz, 1H), 2.85-3.0 (m, 2H),3.19 (m, 1H), 3.38 (m, 2H), 7.15-7.35 (m, 10H). Mass spectrum: (M+H)⁺=271.

G. (2S,4S)-2,4-Bis-(N-(Cbz-valinyl)-amino)-1,5-diphenyl-3-hydroxypentane

A solution of 0.65 g (2.4 mmol) of the resultant compound of Example 6F,2.68 g (7.2 mmol) of N-Cbz-valine p-nitrophenyl ester and 1.34 ml (9.6mmol) of triethylamine in 6 ml of tetrahydrofuran was heated at refluxunder N₂ atmosphere for 16 h. The resulting suspension was cooled,diluted with 30 ml of tetrahydrofuran, treated with 10 ml of 3M aqueousNaOH, and stirred at ambient temperature for 3 h. The mixture wasdiluted with 250 ml of chloroform, washed with four 100 ml portions of0.5M aqueous NaOH, dried over MgSO₄, and concentrated in vacuo. Silicagel chromatography of the residue using 5% methanol in dichloromethaneprovided 1.70 g (96%) of the desired compound as a white solid, m.p.198°-200° C. Mass spectrum (M+H)⁺ =737.

Anal. Calcd. for C₄₃ H₅₂ N₄ O₇.0.5H₂ O: C, 69.24; H, 7.16; N, 7.51.Found: C, 69.40; H, 7.29; N, 7.47.

H. (2S,4S)-2,4-Bis-(N-(valinyl)-amino)-1,5-diphenyl-3-hydroxypentane

A mixture of 1.65 g (2.24 mmol) of the resultant compound of Example 6Gand 165 mg of 10% palladium on carbon in 80 ml of methanol was stirredrapidly under an H₂ atmosphere for 16 h. The resulting solution wasfiltered through Celite and concentrated in vacuo to provide 1.04 g(99%) of the desired compound as a white solid, m.p. 131°-132° C.

I.(2S,4S)-2,4-Bis-(N-(N-(trans-3-(3-pyridinyl)-2-propenoyl)-valinyl)amino)-1,5-diphenyl-3-hydroxypentane

A mixture of 100 mg (0.213 mmol) of the resultant compound of Example6H, 95.5 mg (0.64 mmol) of trans-3-(3-pyridyl)acrylic acid, and 86.5 mg(0.64 mmol) of 1-hydroxybenzotriazole monohydrate in 2 ml of drydimethylformamide was cooled under N₂ atmosphere to 0° C. and treatedwith 122.7 mg (0.64 mmol) of ethyl(dimethylaminopropyl)carbodiimide. Theresulting solution was stirred at 0° C. for 0.5 h, then at ambienttemperature for 16 h. The resulting mixture was concentrated in vacuo,and the residue was treated with saturated aqueous NaHCO₃ and extractedwith five 10 ml portions of 10% methanol in dichloromethane. Thecombined organic layers were dried over Na₂ SO₄ and concentrated. Silicagel chromatography of the residue using 10% methanol in dichloromethaneprovided 132 mg (85%) of the desired compound as a white solid, m.p.271°-273° C. (dec). Mass spectrum: (M+H)⁺ =731.

EXAMPLE 7(2S,4S)-2,4-Bis-(N-(N-(trans-3-(2-pyridinyl)-2-propenoyl)valinyl)amino)-1,5-diphenyl-3-hydroxypentane

Using the procedure of Example 6I but replacingtrans-3-(3-pyridyl)acrylic acid with the resultant compound of Example5B provided, after silica gel chromatography using 10% methanol indichloromethane, 155 mg (99%) of the desired compound, m.p. 257°-259° C.(dec). Mass spectrum: (M+H)⁺ =731.

EXAMPLE 8 A. trans-Ethyl 3-(4-Pyridyl)acrylate

Using the procedure of Example 5A but replacingpyridine-2-carboxaldehyde with pyridine-4-carboxaldehyde provided thedesired compound.

B. trans-3-(4-Pyridyl)acrylic Acid

Using the procedure of Example 5B with the resultant compound of Example8A provided the desired compound.

C.(2S,4S)-2,4-Bis-(N-(N-(trans-3-(4-pyridinyl)-2-propenoyl)-valinyl)amino)-1,5-diphenyl-3-hydroxypentane

Using the procedure of Example 6I but replacingtrans-3-(3-pyridyl)acrylic acid with trans-3-(4-pyridyl)acrylic acidprovided the desired compound, m.p. 250°-251° C. (dec) in 84% yield.Mass spectrum: (M+H)⁺ =731.

EXAMPLE 9 A. N-((4-Phenylpiperazin-1-yl)carbonyl)-valine Methyl Ester

A solution of 2.016 g (12.8 mmol) of the resultant compound of Example2A in 50 ml of dichloromethane was treated with 1.96 ml (12.6 mmol) of1-phenylpiperazine. After being stirred at ambient temperature for 1 h,the solution was diluted with dichloromethane, washed with water, driedover Na₂ SO₄, and concentrated in vacuo. Purification by silica gelchromatography using 25% ethyl acetate in chloroform provided thedesired compound. ¹ H NMR (CDCl₃) δ 0.93 (d, J=7 Hz, 3H), 0.97 (d, J=7Hz, 3H), 2.15 (m, 1H), 3.20 (dd, J=6, 5 Hz, 4H), 3.58 (m, 4H), 3.74 (s,3H), 4.48 (dd, J=8, 5 Hz, 1H), 5.00 (br d, J=8 Hz, 1H), 6.90 (t, J=7 Hz,1H), 6.93 (d, J=7 Hz, 1H), 7.29 (m, 2H). Mass spectrum: (M+H)⁺ =320.

B. N-((4-Phenylpiperazin-1-yl)carbonyl)-valine

Using the procedure of Example 3E with the resultant compound of Example9A provided the desired compound as a foam.

C. N-((4-Phenylpiperazin-1-yl)carbonyl)-valine p-Nitrophenyl Ester

Using the procedure of Example 3F with the resultant compound of Example9B provided the crude desired compound.

D.(2S,3R,4R,5S)-2,5-Bis-(N-(N-((4-phenylpiperazin-1-yl)carbonyl)-valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane

A solution of 0.2 g of the resultant compound of Example 9C in 1 ml of1:1 tetrahydrofuran:dimethyl-formamide was treated with 55 mg (0.11mmol) of the resultant compound of Example 4A and stirred at ambienttemperature for 16 h. The resulting solution was concentrated in vacuo,and the residue was purified by silica gel chromatography using firstchloroform followed by 3% methanol in chloroform to provide 140 mg (87%)of the desired compound, m.p. 172°-173° C. Mass spectrum: (M+H)⁺ =875.

EXAMPLE 10 A. N-((4-Benzylpiperazin-1-yl)carbonyl)-valine Methyl Ester

A solution of 1.2 g (7.64 mmol) of the resultant compound of Example 2Ain 50 ml of dichloromethane was treated with 1.33 ml (7.64 mmol) of1-benzylpiperazine. After being stirred at ambient temperature for 16 h,the solution was diluted with chloroform, washed with water, dried overNa₂ SO₄, and concentrated in vacuo. Purification by silica gelchromatography using first 50% ethyl acetate in chloroform followed by5% methanol in chloroform provided 1.72 g (68%) of the desired compoundas an oil.

B. N-((4-Benzylpiperazin-1-yl)carbonyl)-valine

Using the procedure of Example 3E with the resultant compound of Example10A provided the desired compound as a foam.

C. N-((4-Benzylpiperazin-1-yl)carbonyl)-valine p-Nitrophenyl

Using the procedure of Example 3F with the resultant compound of Example10B provided the crude desired compound.

D.(2S,3R,4R,5S)-2,5-Bis-(N-(N-((4-benzylpiperazin-1-yl)carbonyl)-valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane

Using the procedure of Example 3G but replacing the resultant compoundof Example 1E with the resultant compound of Example 4A and replacingthe resultant compound of Example 3F with the resultant compound ofExample 10C provided, after silica gel chromatography using first 3%then 5% methanol in chloroform, the desired compound, m.p. 178°-179° C.,in 97% yield. Mass spectrum: (M+H)⁺ =903.

Anal. Calcd for C₅₂ H₇₀ N₈ O₆.1.00H₂ O: C, 67.80; H, 7.88; N, 12.16.Found: C, 67.82; H, 7.78; N, 12.02.

EXAMPLE 11 A.(2S,3R,4R,5S)-2,5-Bis-(N-Cbz-amino)-3,4-bis-(mesyloxy)-1,6-diphenylhexane

A slurry of 1.50 g (2.64 mmol) of(2S,3R,4R,5S)-2,5-bis-(N-Cbz-amino)-3,4-dihydroxy-1,6-diphenylhexane in50 ml of anhydrous dichloromethane was cooled to 0° C. and treatedsequentially with 0.43 ml of methanesulfonyl chloride, 64 mg of4-dimethylaminopyridine and 1.1 ml of triethylamine. The resultingmixture was stirred for 15 h with the temperature being allowed toslowly climb to ambient temperature. After treatment with aqueous NH₄Cl, the separated organic layer was washed with aqueous NaHCO₃, driedover MgSO₄, and concentrated in vacuo to provide 1.70 g (90%) of thedesired compound, m.p. 153°-155° C. ¹ H NMR (CDCl₃) δ 2.73 (m, 2H), 2.92(m, 2H), 3.09 (s, 6H), 4.61 (m, 2H), 4.83-5.06 (m, 8H), 7.12-7.37 (m,20H).

B. (4S,5S,4'S,5'S)-4,4'-Dibenzyl-5,5'-bis-(oxazolidin-2-one)

A solution of 0.2 g of the resultant compound of Example 11A in 15 ml ofdimethylformamide was heated at 120° C. under N₂ atmosphere for 18 h.After removal of the solvent, the residue was recrystallized from ethylacetate/hexane to provide 46 mg of the desired compound.

C. (2S,3S,4S,5S)-2,5-Diamino-3 4-dihydroxy-1,6-diphenylhexane

Using the procedure of Example 1E but replacing the resultant compoundof Example 1D with either(2S,3S,4S,5S)-2,5-bis-(N-Cbz-amino)-3,4-dihydroxy-1,6-diphenylhexane orwith the resultant compound of Example 11B provided the desiredcompound. ¹ H NMR (CDCl₃) δ 2.63 (dd, J=14, 11 Hz, 2H), 2.85 (dd, J=14,4 HZ, 2H), 3.60 (dt, J=11, 4 Hz, 2H), 3.92 (d, J=3 Hz, 2H), 7.2-7.4 (m,10H). Mass spectrum: (M+H)⁺ =301.

D.(2S,3S,4S,5S)-2.5-Bis-(N-(N-((4-phenylpiperazin-1-yl)carbonyl)-valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane

A solution of 105 mg (0.35 mmol) of the resultant compound of Example11C in 3 ml of dimethylformamide was treated with 0.5 g of the resultantcompound of Example 9C. After being stirred at ambient temperature underN₂ atmosphere for 16 h, the resulting mixture was diluted with ethylacetate and washed with five portions of 0.1M aqueous K₂ CO₃. The solidproduct, which was not soluble in ethyl acetate, was collected byfiltration, washed on the filter with water, digested on the filter twotimes with ether and filtered to provide the desired compound as a whitesolid, m.p. 165°-166° C.

EXAMPLE 12(2S,3S,4S,5S)-2,5-Bis-(N-(N-((4-benzylpiperazin-1-yl)carbonyl)-valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane

A solution of 80 mg (0.267 mmol) of the resultant compound of Example11C in 3 ml of dimethylformamide was treated with 375 mg of theresultant compound of Example 10C. After being stirred at ambienttemperature under N₂ atmosphere for 16 h, the resulting solution wasdiluted with 600 ml of ethyl acetate, washed with three portions ofaqueous NaHCO₃ and one portion of saturated brine, dried over Na₂ SO₄,and concentrated in vacuo. Purification of the residue on silica gelusing first 3% methanol in chloroform then 5% methanol in chloroformprovided 131 mg (54%) of the pure desired compound as a white solid,m.p. 171°-173° C. Mass spectrum: (M+H)⁺ =903.

Anal. Calcd for C₅₂ H₇₀ N₈ O₆.1.00H₂ O: C, 67.80; H, 7.88; N, 12.16.Found: C, 68.08; H, 7.77; N, 11.91.

EXAMPLE 13 A.(4S,5S,1'R,2'S)-5-(1-Acetoxy-2-(N-Cbz-amino)-3-phenylpropyl)-4-benzyl-oxazolidin-2-one

A suspension of 5.02 g (8.80 mmol) of(2S,3R,4R,5S)-2,5-bis-(N-Cbz-amino)-3,4-dihydroxy-1,6-diphenylhexane in400 ml of acetonitrile was treated dropwise with 3 ml (20 mmol) of(α-acetoxyisobutyryl bromide. The resulting solution was stirred underN₂ atmosphere at ambient-temperature for 2 h, filtered to remove tracesof solid starting material, quenched cautiously with 100 ml of aqueousNaHCO₃, and concentrated in vacuo to a volume of 100 ml. The resultingmixture was extracted with two 100 ml portions of dichloromethane, driedover Na₂ SO₄, and concentrated in vacuo. The residue was purified bysilica gel chromatography using first 10% then 25% ethyl acetate indichloromethane to provide 3.15 g (71%) of the desired compound as awhite foam. ¹ H NMR (CDCl₃) δ 2.09 (s, 3H), 2.53 (br t, J=12 Hz, 1H),2.72 (dd, J=13, 3 Hz, 1H), 2.83 (dd, J=14, 8 Hz, 1H), 2.95 (dd, J=14, 7Hz, 1H), 3.95 (m, 1H), 4.45 (m, 1H), 4.8 (m, 2H), 5.0-5.1 (m, 3H), 5.29(dd, J=9, 3 Hz, 1H), 7.0-7.4 (m, 10H). Mass spectrum: (M+NH₄)⁺ =520.

B.(2S,3R,4R,5S)-2,5-Bis-(N-Cbz-amino)-1,6-diphenyl-2-hydroxy-3-mesyloxyhexane

A slurry of 1.098 g (1.93 mmol) of(2S,3R,4R,5S)-2,5-bis-(N-Cbz-amino)-3,4-dihydroxy-1,6-diphenylhexane in50 ml of anhydrous dichloromethane was treated sequentially with 0.313ml of methanesulfonylchloride, 0.546 ml of triethylamine and 23 mg of4-dimethylaminopyridine. After being stirred for 24 h at ambienttemperature, the solution was washed sequentially with aqueous NH₄ Cland aqueous NaHCO₃, dried over MgSO₄, and concentrated in vacuo. Theresidue was purified by silica gel chromatography using 5% ethyl acetatein dichloromethane to provide 560 mg (45%) of the desired compound, m.p.68°-71° C. ¹ H NMR (CDCl₃) δ 2.7-3.0 (m, 4H), 3.17 (s, 3H), 3.69 (m,1H), 3.92 (m, 1H), 4.19 (br s, 1H), 4.45 (m, 1H), 4.68 (m, 1H),4.87-5.09 (m, 6H), 7.1-7.4 (m, 20H).

C. (4S,5S,1'R,2'S)-4-Benzyl-5-(2-(N-Cbz-amino)-(1-hydroxy-3-phenylpropyl)-oxazolidin-2-one

A solution of 320 mg (0.49 mmol) of the resultant compound of Example13B in 15 ml of acetonitrile was heated at reflux under N₂ atmospherefor 18 h. After being allowed to cool, the solvent was removed in vacuoand the residue was recrystallized from ethyl acetate/hexane to provide89 mg (39%) of the desired compound.

D. (2S,3R,4S,5S)-2,5-Diamino-3,4-dihydroxy-1,6-diphenylhexane

Using the procedure of Example 1E but replacing the resultant compoundof Example 1D with either the resultant compound of Example 13A or theresultant compound of Example 13C provided the desired compound mixedwith benzyl alcohol. Purification of a small portion by silica gelchromatography using 5% methanol/2% isopropylamine in chloroformprovided the pure desired compound., m.p. 115°-119° C. ¹ H NMR (CDCl₃) δ2.46 (dd, J=14, 9 Hz, 1H), 2.61 (dd, J=14, 11 Hz, 1H), 3.02 (td, J=9, 3Hz, 1H), 3.19 (dd, J=14, 4 Hz, 1H), 3.35-3.4 (m, 2H), 3.51 (t, J=9 Hz,1H), 3.76 (dd, J=9, 3 Hz, 1H), 7.2-7.4 (m, 10H).

E.(2S,3R,4S,5S)-2,5-Bis-(N-(N-((4-benzylpiperazin-1-yl)carbonyl)-valinyl)-amino)-3,4-dihydroxy-1,6-diphenylhexane

Using the procedure of Example 3G but replacing the resultant compoundof Example 1E with the resultant compound of Example 13D and replacingthe resultant compound of Example 3F with the resultant compound ofExample 10C provided the desired compound.

EXAMPLE 14 A. Thiazole-2-carboxaldehyde

A solution of 5 g (60 mmol) of thiazole in 20 ml of anhydrous ether wascooled under N₂ atmosphere to -78° C. and treated over a period of 20min with a solution of 26 ml of n-butyllithium (2.5M in hexane) dilutedwith 10 ml of ether. After addition, the solution was stirred for 30 minand treated with a solution of 6.0 ml (60 mmol) of N-formylmorpholine in10 ml of anhydrous ether over a period of 10 min. The resulting solutionwas allowed to warm to ambient temperature over a period of 4 h, afterwhich it was quenched at 0° C. with 4N aqueous HCl. The mixture wasdiluted with 4N HCl, after which the aqueous layer was washed withether, neutralized to pH 8 with aqueous NaOH and aqueous NaHCO₃,extracted with four 50 ml portions of ether, dried over MgSO₄, andconcentrated in vacuo. The crude product thus obtained (5.02 g, 76%) asa brown solid was of sufficient purity for the next step.

B. trans-Methyl 3-(thiazol-2-yl)-2-propenoate

Using the procedure of Example 5A but replacing triethylphosphonoacetatewith trimethylphosphonoacetate and replacing pyridine-2-carboxaldehydewith the resultant compound of Example 14A provided, after silica gelchromatography using 4:1 hexane:ethyl acetate, a 40% yield of thedesired compound as a yellow crystalline solid, m.p.75°-75.5° C. ¹ H NMR(CDCl₃) δ 3.83 (s, 3H), 6.73 (d, J=15 Hz, 1H), 7.45 (d, J=3 Hz, 1H),7.80 (d, J=15 Hz, 1H), 7.93 (d, J=3 Hz, 1H).

C. trans-3-(Thiazol-2-yl)-2-propenoic Acid

A solution of 1.46 g (8.6 mmol) of the resultant compound of Example 14Bin 10 ml of 1,4-dioxane and 5 mol of water was treated with 0.73 g (17mmol) of lithium hydroxide monohydrate and stirred at ambienttemperature for 16 h. The resulting solution was concentrated in vacuoto a volume of 5 ml and acidified to pH 2 with 4N HCl. The precipitatethus obtained was filtered and dried in vacuo to provide 1.2 g (90%) ofthe desired compound as an off-white solid, m.p. 185.5°-187° C. ¹ H NMR(d₆ -DMSO) δ 6.67 (d, J=15 Hz, 1H), 7.70 (d, J=15 Hz, 1H), 7.95 (d, J=3Hz, 1H), 8.01 (d, J=3 Hz, 1H), 12.81 (br s, 1H). Mass spectrum: (M+H)⁺=156.

D.(2S,3R,4R,5S)-2,5-Bis-(N-(N-(trans-3-(thiazol-2-yl)-2-propenoyl)-valinyl)-amino)-3,4-dihydroxy-1,6-diphenylhexane

Using the procedure of Example 6I but replacingtrans-3-(3-pyridyl)acrylic acid with the resultant compound of Example14C and replacing the resultant compound of Example 6H with theresultant compound of Example 4C provided the desired compound,m.p.>260° C. Mass spectrum: (M+H)⁺ =773.

EXAMPLE 15 A.(2S,3S,4R,5S)-3-Acetoxy-2,5-bis-(N-Cbz-amino)-3-bromo-1,6-diphenylhexane

Using the procedure of Example 1C but replacing(2S,3R,4R,5S)-2,5-bis-(N-Cbz-amino)-3,4-dihydroxy-1,6-diphenylhexanewith(2S,3S,4S,5S)-2,5-bis-(N-Cbz-amino)-3,4-dihydroxy-1,6-diphenylhexaneprovided the desired compound in 11% yield along with(4S,5R,1'S,2'S)-5-(1-acetoxy-2-(N-Cbz-amino)-3-phenylpropyl)-4-benzyl-oxazolidin-2-onein 35% yield.(2S,3S,4R,5S)-3-Acetoxy-2,5-bis-(N-Cbz-amino)-3-bromo-1,6-diphenylhexane:¹ H NMR (CDCl₃) δ 2.05 (s, 3H), 2.57 (dd, J=13, 8 Hz, 1H), 2.74 (m, 2H),2.92 (dd, J=14, 7 Hz, 1H), 3.82 (d, J=9 Hz, 1H), 4.32 (br q, 1H), 4.64(m, 1H), 4.9-5.1 (m, 6H), 5.33 (br d, 1H), 7.0-7.4 (m, 20H). Massspectrum: (M+H)⁺ =673, 675.

B. (2S,3R,5S)-3-Acetoxy-2,5-bis-(N-Cbz-amino)-1,6-diphenylhexane

Using the procedure of Example 1D but replacing the resultant compoundof Example 1C with the resultant compound of Example 15A provided thedesired compound. Mass spectrum: (M+NH₄)⁺ =612.

C. (2S,3R,5S)-2,5-Diamino-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1E but replacing the resultant compoundof Example 1D with the resultant compound of Example 15B provided, aftersilica gel chromatography using first 2% isopropylamine in chloroformfollowed by 2% methanol and 2% isopropylamine in chloroform, the desiredcompound contaminated with Sn salts. ¹ H NMR (CDCl₃) δ 1.85 (m, 1H),2.43 (dd, J=13, 10 Hz, 1H), 2.66 (dd, J=14, 9 Hz, 1H), 2.86 (dd, J=14, 4Hz, 1H), 3.0-3.1 (m, 2H), 3.49 (m, 1H), 3.89 (m, 1H), 7.2-7.4 (m, 10H)Mass spectrum: (M+H)⁺ =285.

D.(2S,3R,5S)-2,5-Bis-(N-(N-((N-methyl-N-((2-pyridinyl)-methyl)-amino)-carbonyl)-valinyl)-amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 3G but replacing the resultant compoundof Example 1E with the resultant compound of Example 15C provided, aftersilica gel chromatography using 1.5% methanol in chloroform followed by2% methanol in chloroform, the desired compound, m.p. 92°-96° C., in 65%yield. Mass spectrum: (M+H)⁺ =779.

EXAMPLE 16 A. α-Isocyanato-isoleucine Methyl Ester

Using the procedure of Example 2A but replacing L-valine methyl esterhydrochloride with L-isoleucine methyl ester hydrochloride provided thedesired compound as an oil.

B. N-((N-Methyl-N-((2-pyridinyl)methyl)amino)carbonyl)-isoleucine MethylEster

Using the procedure of Example 3D but replacing the resultant compoundof Example 2A with the resultant compound of Example 16A provided thedesired compound. ¹ H NMR (CDCl₃) δ 0.92 (t, J=7 Hz, 3H), 0.94 (d, J=7Hz, 3H), 1.21 (m, 1H), 1.46 (m, 1H), 1.90 (m, 1H), 3.02 (s, 3H), 3.71(s, 3H), 4.46 (dd, J=8, 5 Hz, 1H), 4.53 (s, 2H), 6.15 (br, 1H), 7.22(dd, J=7, 5 Hz, 1H), 7.27 (d, J=7 Hz, 1H), 7.69 (td, J=7, 2 Hz, 1H),8.55 (br d, 1H).

C. N-((N-Methyl-N-((2-pyridinyl)methyl)amino)carbonyl)-isoleucinep-Nitrophenyl Ester

Using the procedures of Example 3E and Example 3F with the resultantcompound of Example 16B provided the crude desired compound.

D.(2S,3S,5S)-2,5-Bis-(N-(N-((N-methyl-N-((2-pyridinyl)methyl)amino)carbonyl)isoleucinyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 3G but replacing the resultant compoundof Example 3F with the resultant compound of Example 16C provided, aftersilica gel chromatography using 2% methanol in chloroform, the desiredcompound in 68% yield. The pure compound melted at 143°-145° C.,resolidified, and melted again at 173°-174° C. Mass spectrum: (M+H)⁺=807.

EXAMPLE 17 (2S,3S,5S)-2,5-Bis-(N-Cbz-amino)-1,6-diphenyl-3-hydroxyhexane

A solution of 200 mg (0.34 mmol) of the resultant compound of Example 1Din 4 ml of methanol was treated with 2 ml of concentrated aqueousammonium hydroxide. The resulting solution was stirred at ambienttemperature for 6 h, and at 50° C. for 45 min. An additional 1 ml ofconcentrated aqueous ammonium hydroxide was added and heating wascontinued for 1 h. The resulting solution was diluted with 50 ml ofdichloromethane, washed sequentially with water and saturated brine,dried over MgSO₄, and concentrated in vacuo. Silica gel chromatographyof the residue using 25% ethyl acetate in hexane followed by 33% ethylacetate in hexane provided 161 mg (84%) of the desired compound. ¹ H NMR(CDCl₃) δ 1.63 (m, 2H), 2.73 (m, 2H), 2.85 (m, 2H), 3.05 (br, 1H), 3.64(m, 1H), 3.77 (br q, 1H), 3.93 (br q, 1H), 4.78 (br d, 1H), 5.05 (m,4H), 7.0-7.4 (m, 20H). Mass spectrum: (M+H)⁺ =553.

Anal. Calcd for C₃₄ H₃₆ N₂ O₅ : C, 73.89; H, 6.57; N, 5.07. Found: C,73.81; H, 6.61; N, 5.04.

EXAMPLE 18 A.trans-(2S,5S)-2,5-Bis-(N-(benzyloxycarbonyl)amino)-1,6-diphenyl-3-hexene

A solution of 4.64 g of the resultant compound of Example 15A in 48 mlof acetic acid was treated with 1.33 g of zinc dust and stirred atambient temperature for 3 days. The resulting solution was concentratedin vacuo, taken up in ethyl acetate, washed with saturated aqueousNaHCO₃, dried over MgSO₄, and concentrated in-vacuo to provide 3.27 g(89%) of the desired compound.

B. trans-(2S,5S)-2,5-Diamino-1,6-diphenyl-3-hexene

A solution of 3.27 g of the resultant compound of Example 18A in 75 mlof 30% HBr in acetic acid was allowed to stand at ambient temperaturefor 16 h. The resulting solution was concentrated in vacuo, and theresidue was washed with hexane to remove benzyl bromide. The solid wasthen taken up in 1N NaOH, extracted with three 100 ml portions ofdichloromethane, dried over Na₂ SO₄, and concentrated. Silica gelchromatography using first 2% isopropylamine in chloroform, then 2%methanol/2% isopropylamine in chloroform provided 1.35 g (83%) of thedesired compound.

C.trans-(2S,5S)-2,5-Bis-(N-(N-((N-methyl-N-((2-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-1,6-diphenyl-3-hexene

Using the procedure of Example 3G but replacing the resultant compoundof Example 1E with the resultant compound of Example 18B provided, aftersilica gel chromatography using first 1.5% methanol in chloroform then3% methanol in chloroform, 86 mg (75%) of the desired compound as awhite solid. Mass spectrum: (M+H)⁺ =761.

EXAMPLE 19 A. trans-Ethyl 3-((Thiazol-2-yl]-amino)-2-propenoate

A solution of 2.3 g of 2-aminothiazole and 1.55 ml of ethyl propiolatein 10 ml of dichloromethane and 5 ml of dimethylformamide was stirred atambient temperature for 3 days. The resulting mixture was filtered, andthe filtrate was concentrated in vacuo. The residue was chromatographedon silica gel using first 20% then 40% ethyl acetate in hexane toprovide 1.54 g (51%) of the desired compound. ¹ H NMR (CDCl₃) δ 1.30 (t,J=7 Hz, 3H), 4.22 (q, J=7 Hz, 2H), 5.79 (d, J=15 Hz, 1H), 6.03 (d, J=5Hz, 1H), 6.68 (d, J=5 Hz, 1H), 7.47 (br, 1H), 8.17 (d, J=15 Hz, 1H).Mass spectrum: (M+H)⁺ =199.

B. trans-3-((Thiazol-2-yl)-amino)-2-propenoic Acid

Using the procedure of Example 3E but replacing the resultant compoundof Example 3D with the resultant compound of Example 19A provided thedesired compound in 70% yield. ¹ H NMR (d₆ -DMSO) δ 6.08 (d, J=15 Hz,1H), 6.50 (d, J=5 Hz, 1H), 7.37 (d, J=5 Hz, 1H), 8.01 (d, J=15 Hz, 1H),9.4 (br, 1H). Mass spectrum: (M+H)⁺ =171.

C.(2S,3R,4R,5S)-2,5-Bis-(N-(N-(trans-3-((thiazol-2-yl)amino)-2-propenoyl)-valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane

Using the procedure of Example 6I but replacing the resultant compoundof Example 6H with the resultant compound of Example 4C and replacingtrans-3-(3-pyridyl)acrylic acid with the resultant compound of Example19B provided the desired compound.

EXAMPLE 20(2S,3S,5S)-3-Acetoxy-2,5-bis-(N-(N-((2-pyridinyl)methoxycarbonyl)-valinyl)-amino)-1,6-diphenylhexane

A suspension of 59 mg (0.078 mmol) of the resultant compound of Example2E in 1 ml of dichloromethane was treated sequentially with 0.017 ml(0.16 mmol) of 4-methylmorpholine, 0.007 ml (0.12 mmol) of aceticanhydride, and 5 mg of 4-dimethylaminopyridine. The resulting mixturewas stirred at ambient temperature for 1 h, treated with 10 ml ofaqueous NaHCO₃, stirred for 30 min, extracted with two 20 ml portions ofdichloromethane, dried over Na₂ SO₄, and concentrated in vacuo. Silicagel chromatography of the residue using 3% methanol in chloroformprovided 51.6 mg (83%) of the desired compound.

EXAMPLE 21 (2S,3S,5S)-2,5-Bis-(N-Boc-amino)-1,6-diphenyl-3-hydroxyhexane

A solution of 1.0 g (4.1 mmol) of the resultant compound of Example 1Eand 1.98 g (9.1 mmol) of di-t-butyldicarbonate in 40 ml ofdichloromethane was stirred at ambient temperature for 1 h. The solventwas removed in vacuo, and the residue was chromatographed on silica gelusing 25% ethyl acetate in hexane followed by 33% ethyl acetate inhexane to provide 1.32 g (72%) of the desired compound. ¹ H NMR (CDCl₃)δ 1.39 (s, 18H), 1.62 (t, J=6 Hz, 2H), 2.74 (m, 2H), 2.85 (m, 2H), 3.65(m, 2H), 3.86 (br q, 1H), 4.54 (br, 1H), 4.80 (br d, 1H), 7.05-7.3 (m,10H). Mass spectrum: (M+H)⁺ =485.

Anal. Calcd for C₂₈ H₄₀ N₂ O₅ : C, 69.39; H, 8.32; N, 5.78. Found: C,69.21; H, 8.38; N, 5.73.

EXAMPLE 22(2S,3S,5S)-2,5-Bis-(N-(t-butylacetyl)-amino)-1,6-diphenyl-3-hydroxyhexane

A solution of 150 mg (0.53 mmol) of the resultant compound of Example 1Eand 0.18 ml (1.3 mmol) of triethylamine in 6 ml of dichloromethane wascooled under N₂ atmosphere to -40° C. and treated with 0.15 ml (1.1mmol) of t-butylacetyl chloride. The resulting solution was stirred at-40° C. for 30 min, diluted with 50 ml of dichloromethane, washedsequentially with water and saturated brine, dried over MgSO₄, andconcentrated in vacuo. Silica gel chromatography of residue using first25% then 33% ethyl acetate in hexane provided 216 mg (85%) of thedesired compound. ¹ H NMR (CDCl₃) δ 0.89 (s, 9H), 0.95 (s, 9H), 1.67 (m,2H), 1 93 (s, 2H), 1 97 (s, 2H), 2 76 (AA', 2H) 2.88 (d, J=7 Hz, 2H),3.61 (br t, 1H), 3.97 (br q, 1H), 4.08 (m, 1H), 4.62 (br, 1H), 5.55 (brd, J=7 Hz, 1H), 5.77 (br d, J=9 Hz, 1H), 7.05-7.3 (m, 10H). Massspectrum: (M+H)⁺ =481.

Anal. Calcd for C₃₀ H₄₄ N₂ O₃ : C, 74.96; H, 9.23; N, 5.83. Found: C,74.41; H, 9.21; N, 5.73.

EXAMPLE 23(2S,3S,5S)-2,5-Bis-(N-((4-pyridinyl)methoxycarbonyl)-amino)-1,6-diphenyl-3-hydroxyhexane

A solution of 0.12 mmol of triphosgene in 2 ml of anhydroustetrahydrofuran was cooled under N₂ atmosphere to -78° C. A solution of0.36 mmol of pyridine-4-methanol and 0.36 mmol of 4-methylmorpholine in1 ml of tetrahydrofuran was added dropwise. The resulting solution wasstirred at -78° C. for 30 min, treated with a solution of 0.18 mmol ofthe resultant compound of Example 1E and 0.36 mmol of 4-methylmorpholinein 1 ml of tetrahydrofuran, and stirred at -100° C. for 2 h. The solventwas then removed in vacuo, and the residue was chromatographed on silicagel to provide the desired compound.

EXAMPLE 24 A. 3-(N-(t-Butyloxycarbonyl)aminomethyl)pyridine

Using the procedure of Example 3A but replacing 2-(aminomethyl)pyridinewith 3-(aminomethyl)pyridine provided the desired compound in 97% yield.¹ H NMR (CDCl₃) δ 1.47 (s, 9H), 4.33 (br d, J=6. Hz, 2H), 4.95 (br, 1H),7.27 (br t, J=6 Hz, 1H), 7.63 (br d, J=8 Hz, 1H), 8.52 (m, 2H).

B. 3-((N-(t-Butyloxycarbonyl)-N-methylamino)methyl)pyridine

Using the procedure of Example 3B but replacing the resultant compoundof Example 3A with the resultant compound of Example 24A provided thedesired compound.

C. 3-(N-Methylamino)methyl)pyridine Dihydrochloride

Using the procedure of Example 3C but replacing the resultant compoundof Example 3B with the resultant compound of Example 24B provided thedesired compound.

D. N-((N-Methyl-N-((3-pyridinyl)methyl)amino)carbonyl)valine MethylEster

Using the procedure of Example 3D but replacing the resultant compoundof Example 3C with the resultant compound of Example 24C provided thedesired compound. ¹ H NMR (CDCl₃) δ 0.90 (d, J=7 Hz, 3H), 0.96 (d, J=7Hz, 3H), 2.16 (pd, J=7, 5 Hz, 1H), 2.93 (s, 3H), 3.74 (s, 3H), 4.49 (dd,J=9, 5 Hz, 1H), 4.54 (s, 2H), 4.95 (br d, J=9 Hz, 1H), 7.28 (td, J=6, 1Hz, 1H), 7.61 (ddd, J=7, 3, 2 Hz, 1H), 8.53 (m, 2H). Mass spectrum:(M+H)⁺ =280.

E. N-((N-Methyl-N-((3-pyridinyl)-methyl)-amino)-carbonyl)-valine

Using the procedure of Example 3E but replacing the resultant compoundof Example 3D with the resultant compound of Example 24D provided thedesired compound.

F. N-((N-Methyl-N-((3-pyridinyl)-methyl)-amino)-carbonyl)-valinep-Nitrophenyl Ester

Using the procedure of Example 3F but replacing the resultant compoundof Example 3E with the resultant compound of Example 24E provided thedesired compound.

G.(2S,3S,5S)-2,5-Bis-(N-(N-((N-methyl-N-((3-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 3G but replacing the resultant compoundof Example 3F with the resultant compound of Example 24F provided, aftersilica gel chromatography using first 2% methanol in chloroform, then 7%methanol in chloroform, and finally 10% methanol in chloroform, thedesired compound (R_(f) 0.19, 10% methanol in chloroform) in 49% yield.

EXAMPLE 25 A. N-((2-Pyridinyl)methoxycarbonyl)-isoleucine Methyl

Using the procedure of Example 2B but replacing the resultant compoundof Example 2A with the resultant compound of Example 16A provided thedesired compound.

D. N-((2-Pyridinyl)methoxycarbonyl)-isoleucine.

Using the procedure of Example 3E but replacing the resultant compoundof Example 3D with the resultant compound of Example 25A provided thedesired compound.

C. N-((2-Pyridinyl)methoxycarbonyl)-isoleucine p-Nitrophenyl

Using the procedure of Example 3F but replacing the resultant compoundof Example 3E with the resultant compound of Example 25B provided thedesired compound.

D.(2S,3S,5S)-2,5-Bis-(N-(N-((2-pyridinyl)methoxycarbonyl)-isoleucinyl)-amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 1E but replacing the resultant compoundof Example 1D with the resultant compound of Example 25C provided, aftertrituration of the residue with 4:1 ethyl acetate:hexane and filtration,the desired compound. Mass spectrum: (M+H)⁺ =791.

Anal. Calcd for C₄₄ H₅₆ N₆ O₇.2H₂ O: C, 64.69; H, 7.40; N, 10.29. Found:C, 64.78; H, 6.90; N, 10.32.

EXAMPLE 26(2S,3S,5S)-3-Acetoxy-2,5-bis-(N-(N-((N-methyl-N-((2-pyridinyl)-methyl)-amino)-carbonyl)-valinyl)-amino)-1,6-diphenylhexane

Using the procedure of Example 20 but replacing the resultant compoundof Example 2E with the resultant compound of Example 3G provided, aftersilica gel chromatography using 3% methanol in chloroform, the desiredcompound in 89% yield. Mass spectrum: (M+H)⁺ =821.

EXAMPLE 27(2S,3S,5S)-2,5-Bis-(N-Boc-amino)-1,6-dicyclohexyl-3-hydroxyhexane

A mixture of 100 mg of the resultant compound of Example 21 and 100 mgof 5% rhodium on carbon in 3 ml of methanol was shaken under 4atmospheres of H₂ for 1 day. The resulting mixture was filtered andconcentrated in vacuo. Silica gel chromatography of the residue using20% ethyl acetate in hexane provided 92 mg (90%) of the desiredcompound. ¹ H NMR (CDCl₃) δ 0.75-1.90 (br envelope, 28H), 1.44 (s, 18H),3.30 (br, 1H), 3.63 (m, 2H), 3.72 (m, 1H), 4.41 (br, 1H), 4.66 (br d,1H). Mass spectrum: (M+H)⁺ =497.

Anal. Calcd for C₂₈ H₅₀ N₂ O₅.0.75H₂ O: C, 66.17; H, 10.21; N, 5.51.Found: C, 65.98; H, 10.42; N, 5.47.

EXAMPLE 28 A. Boc-(L)-(4-thiazolyl)-alaninal

A solution of 5 g of Boc-(L)-(4-thiazolyl)alanine in 25 ml of anhydrousdimethylformamide was treated with 4.1 ml of ethanethiol and 60 mg of4-dimethylaminopyridine. The resulting solution was cooled to 0° C.,treated with 4.5 g of dicyclohexylcarbodiimide, and stirred at 0° C. for20 min and at ambient temperature for 5 h. The mixture was filtered,concentrated, taken up in 5 ml of ethyl acetate, filtered, andconcentrated in vacuo. Silica gel chromatography using 15% ethyl acetatein hexane provided 4.4 g (72%) of Boc-(L)-(4-thiazolyl)alanineethanethiol ester. A portion of the above thioester (0.18 g) wascombined with 0.25 g of 10% palladium on carbon in 3 ml of acetone. Themixture was treated with 0.3 ml of triethylsilane, stirred for 4 h,filtered through Celite, and concentrated in vacuo. Silica gelchromatography using first chloroform then 3% methanol in chloroformprovided 0.1 g (68%) of the desired compound.

B.(2S,3R,4R,5S)-2,5-Bis-(N-Boc-amino)-3,4-dihydroxy-1,6-di-(4-thiazolyl)-hexane

Using the procedure of Example 1B, but replacing Cbz-L-phenylalaninalwith the resultant compound of Example 28A and adding a neutralizationstep after addition of 1N aqueous HCl, provided, after extraction withchloroform, a crude mixture which was purified by silica gelchromatography to give the desired compound.

C.(2S,3S,5S)-2,5-Bis-(N-(N-((2-pyridinyl)methoxycarbonyl)-valinyl)-amino)-1,6-di-(4-thiazolyl)-3-hydroxyhexane

Using sequentially the procedures of Examples 1C, 1D, 1E and 2E butreplacing(2S,3R,4R,5S)-2,5-bis-(N-Cbz-amino)-3,4-dihydroxy-1,6-diphenylhexanewith the resultant compound of Example 28B provided the desiredcompound.

EXAMPLE 29 A.(2S,3R,4R,5S)-2,5-Bis-(N-Cbz-amino)-1,6-di-(4-benzyloxyphenyl)-3,4-dihydroxy-hexane

Using sequentially the procedures of Examples 1A and 1B bun replacingCbz-(L)-phenylalaninol with Cbz-(L)-O-benzyltyrosinol provided a crudemixture which was purified by silica gel chromatography to give thedesired compound.

B. (2S,3S,5S)-2,5-Diamino-1,6-(4-hydroxyphenyl)-3-hydroxyhexane

Using sequentially the procedures of Examples 1C, 1D and 17 butreplacing(2S,3R,4R,5S)-2,5-bis-(N-Cbz-amino)-3,4-dihydroxy-1,6-diphenylhexanewith the resultant compound of Example 29A provided a compound which wastreated with methanol and 10% palladium on carbon, shaken under 4atmospheres of H₂ for 4 h, filtered, and concentrated in vacuo toprovide the desired compound.

C.(2S,3S,5S)-2,5-Bis-(N-(N-((2-pyridinyl)methoxycarbonyl)-valinyl)-amino)-1,6-di-(4-hydroxyphenyl)-3-hydroxyhexane

Using the procedure of Example 2E but replacing the resultant compoundof Example 1E with the resultant compound of Example 29B provided thedesired compound.

EXAMPLE 30 A. N-((2-Pyridinyl)methoxythionocarbonyl)-valine Methyl

A suspension of 1.0 g (5.96 mmol) of (L)-valine methyl ester in 10 ml ofchloroform was cooled to -20° C. and treated with a solution of 0.48 mlof thiophosgene in 5 ml of chloroform. The resulting solution wastreated dropwise with 2.49 ml (17.9 mmol) of triethylamine, stirred at-20° C. for 15 min, then quenched with 10 ml of 0.1M HCl. The chloroformlayer was separated, washed with four 5 ml portions of water, dried overMgSO₄, and concentrated in vacuo to provide 1.01 g of theα-isothiocyanato-(L)-valine methyl ester as an oil. The crude oil (1.01g) was taken up in 10 ml of dichloromethane and added to a mixture of0.81 g (4.15 mmol) of the resultant compound of Example 3C and 1.14 ml(10.4 mmol) of 4-methylmorpholine in 40 ml of dichloromethane. Theresulting mixture was stirred at ambient temperature for 16 h, washedwith three 15 ml portions of water, dried over MgSO₄, and concentratedin vacuo. Silica gel chromatography of the residue using 15% ethylacetate in dichloromethane provided 1.23 g (100%) of the desiredcompound as an oil. ¹ H NMR (CDCl₃) δ 1.02 (d, J=7 Hz, 3H), 1.06 (d, J=7Hz, 3H). 2.33 (m, 1H), 3.40 (s 3H), 3.74 (s, 3H), 4.83 (AA', 2H), 5.10(dd, J=8, 5 Hz, 1H), 7.27 (dd, J=8, 5 Hz, 1H), 7.33 (d, J=8 Hz, 1H),7.73 (br t, J=8 Hz, 1H), 8.56 (dd, J=5, 1 Hz, 1H). Mass spectrum: (M+H)⁺=296.

B. N-((2-Pyridinyl)methoxythionocarbonyl)-valine

Using the procedure of Example 3E but replacing the resultant compoundof Example 3D with the resultant compound of Example 30A provided thedesired compound as a foam. ¹ H NMR (CDCl₃) δ 1.04 (d, J=7 Hz, 3H), 1.08(d, J=7 Hz, 3H), 2.41 (m, 1H), 3.41 (s, 3H), 4.80 (d, J=15 Hz, 1H), 4.94(br d, J=15 Hz, 1H), 5.11 (dd, J=8, 5 Hz, 1H), 7.29 (ddd, J=8, 5, 1 Hz,1H), 7.34 (d, J=8 Hz, 1H), 7.76 (td, J=8, 2 Hz, 1H), 8.19 (br, 1H), 8.55(ddd, J=5, 2, 1 Hz, 1H). Mass spectrum: (M+H)⁺ =282.

C.(2S,3S,5S)-2,5-Bis-(N-(N-((2-pyridinyl)methoxythionocarbonyl)-valinyl)-amino)-1,6-diphenyl-3-hydroxyhexane

Using sequentially the procedures of Examples 3F and 3G but replacingthe resultant compound of Example 3E with the resultant compound ofExample 30B provided the desired compound.

EXAMPLE 31 A.(2S,3S,5S)-2,5-Bis-(N-(Cbz-threoninyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 6I but replacing the resultant compoundof Example 6H with the resultant compound of Example 1E and replacingtrans-3-(3-pyridyl)acrylic acid with Cbz-(L)-threonine provided, aftersilica gel chromatography, the desired compound.

EXAMPLE 32(2S,3S,5S)-2,5-Bis-(N-(Cbz-valinyl)-amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 6G but replacing the resultant compoundof Example 6F with the resultant compound of Example 1E provided thedesired compound.

EXAMPLE 33(2S,3S,5S)-2,5-Bis-(N-(valinyl)-amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 6H but replacing the resultant compoundof Example 6G with the resultant compound of Example 32 provided thedesired compound.

EXAMPLE 34 A. 3-(Thiazol-2-yl)-propanoic Acid

According to procedure of Johes, et. al. (J. Am. Chem. Soc. 1950, 72,4526), a solution of 0.5 g of the resultant compound of Example ! 4C and0.15 g of sodium hydroxide in 4 ml of water was treated with 0.10 g ofRaney nickel and shaken under 3 atmospheres of hydrogen for 16 h. Themixture was filtered, and the filtrate was neutralized with 4N HCl,concentrated in vacuo, and acidified to pH 2 with 4N HCl. The resultingprecipitate was filtered to give 0.17 g (34%) of the desired compound asa white solid.

B.(2S,3S,5S)-2,5-Bis-(N-(N-(3-(thiazol-2-yl)propanoyl)valinyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 6I but replacing the resultant compoundof Example 6H with the resultant compound of Example 33 and replacingtrans-3-(3-pyridyl)acrylic acid with the resultant compound of Example34A provided the desired compound.

EXAMPLE 35(2S,3S,5S)-2,5-Bis-(N-(N-((2-pyridinyl)methoxycarbonyl)-valinyl)-amino)-1,6-diphenyl-3-(trifluoroacetoxy)-hexane

Using the procedure of Example 20 but replacing acetic anhydride withtrifluoroacetic anhydride and quenching the reaction with pH 6 buffergave a two-layer mixture. The organic layer was diluted withdichloromethane, separated, dried over Na₂ SO₄, and concentrated invacuo to provide the desired compound. ¹ H NMR (CDCl₃) δ 0.69 (d, 3H),0.72 (d, 3H), 0.81 (d, 3H), 0.85 (d, 3H), 1.63 (m, 1H), 1.94 (m, 1H),2.08 (m, 2H), 2.66 (m, 2H), 2.81 (m, 2H), 3.81 (dd, 1H), 3.87 (dd, 1H),4.53 (br, 1H), 5.01 (m, 2H), 5.22-5.28 (m, 6H), 5.92 (br, 1H), 6.04 (brd, 1H), 7.12-7.24 (m, 12H), 7.34 (br t, 2H), 7.72 (td, 2H), 8.60 (br d,2H). Mass spectrum: (M+H)⁺ =849.

EXAMPLE 36(2S,3S,5S)-2,5-Bis-(N-(N-((N-methyl-N-((2-pyridinyl)-methyl)-amino)-carbonyl)-valinyl)-amino)-1,6-diphenyl-3-(trifluoroacetoxy)-hexane

Using the procedure of Example 20 but replacing acetic anhydride withtrifluoroacetic anhydride, replacing the resultant compound of Example2E with the resultant compound of Example 3G, and quenching the reactionwith pH 6 buffer gave a two-layer mixture. The organic layer was dilutedwith dichloromethane, separated, dried over Na₂ SO₄, and concentrated invacuo to provide the desired compound.

EXAMPLE 37 A. ((3-Pyridinyl)methyl)-(4-nitrophenyl)carbonate

A solution 20 g (0.1 mol) of (4-nitrophenyl)chloroformate in 150 ml ofdichloromethane was cooled to 0° C. and treated sequentially with 8.0 ml(0.083 mol) of pyridine-3-methanol and 11 ml (0.1 mol) of4-methylmorpholine. After addition, the solution was allowed to come toambient temperature, stirred for 0.5 h, diluted with dichloromethane,washed sequentially with aqueous NaHCO₃ and water, dried over Na₂ SO₄,and concentrated in vacuo. The residue was broken up, triturated with3:1 hexane :ethyl acetate, and filtered. The resulting solid wasdissolved in a minimum amount of boiling ethyl acetate/hexane, filteredhot to remove an insoluble dark oil, and allowed to cool. The desiredcrystalline product (18.65 g, 82%) was collected by filtration.

B.(2S,3S,5S)-5-Amino-2-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneand(2S,3S,5S)-2-Amino-5-(N-((3-pyridinyl)methoxycarbonyl)-amino)-1,6-diphenyl-3-hydroxyhexane

A solution of 1.5 g (5.28 mmol) of the resultant compound of Example 1Ein 10 ml of tetrahydrofuran was treated dropwise over a 5 hour periodwith a solution of 1.6 g (5.8 mmol) of the resultant compound of Example37A in 10 ml of tetrahydrofuran. After addition, the resulting solutionwas stirred at ambient temperature for 16 h and concentrated in vacuo.Silica gel chromatography using a gradient of 2-3.5% methanol inchloroform provided a mixture of the two desired compounds. Silica gelchromatography of the mixture using first 2% isopropylamine indichloromethane followed by 2% isopropylamine/2% methanol indichloromethane provided 0.38 g (16%) of(2S,3S,5S)-5-amino-2-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneand 0.87 g (36%) of(2S,3S,5S)-2-amino-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

C.(2S,3S,5S)-2-(N-(N-((N-Methyl-N-((2-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

A solution of 1.2 g (2.86 mmol) of(2S,3S,5S)-2-amino-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanein 20 ml of tetrahydrofuran was treated with 1.55 g (4.01 mmol) of theresultant compound of Example 3F. The resulting solution was stirred atambient temperature for 96 h, treated with aqueous NaHCO₃, extractedwith chloroform, dried over Na₂ SO₄, and concentrated in vacuo. Theresidued was purified by silica gel chromatography using first 2% then4% methanol in chloroform to provide 1.75 g (92%) of the desiredcompound (R_(f) 0.28, 10% methanol in chloroform) as a white solid, m.p.69°-71° C. Mass spectrum: (M+1)⁺ =667.

Anal. Calcd for C₃₈ H₄₆ N₆ O₅.0.5H₂ O: C, 67.54; H, 7.01; N, 12.44.Found: C, 67.54; H, 6.83; N, 12.33.

EXAMPLE 38(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

A solution of 0.95 g (2.27 mmol) of(2S,3S,5S)-5-amino-2-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanein 15 ml of tetrahydrofuran was treated with 1.22 g (3.17 mmol) of theresultant compound of Example 3F. The resulting solution was stirred atambient temperature for 24 h, treated with aqueous NaHCO₃, extractedwith chloroform, dried over Na₂ SO₄, and concentrated in vacuo. Theresidued was purified by silica gel chromatography using first 2% then4% methanol in chloroform to provide 1.46 g (94%) of the desiredcompound (R_(f) 0.26, 10% methanol in chloroform) as a white solid, m.p.58°-61° C. Mass spectrum: (M+1)⁺⁼ 667.

Anal. Calcd for C₃₈ H₄₆ N₆ O₅.1.1H₂ O: C, 66.47; H, 7.08; N, 12.24 .Found: C, 66.12; H, 6.68; N, 12.10.

EXAMPLE 39(2S,3S,5S)-2-(N-(N-((2-Pyridinyl)methoxycarbonyl)valinyl)amino)-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 37C but replacing the resultant compoundof Example 3F with the resultant compound of Example 2D provided, aftersilica gel chromatography using a gradient of 2-5% methanol inchloroform, 104 mg (95%) of the desired compound (R_(f) 0.30, 10%methanol in chloroform) as a white solid, m.p. 169°-171° C. Massspectrum: (M+1)⁺ =654.

Anal. Calcd for C₃₇ H₄₃ N₅ O₆.0.5H₂ O: C, 67.05; H, 6.69; N, 10.51.Found: C, 66.98; H, 6.53; N, 10.57.

EXAMPLE 40(2S,3S,5S)-5-(N-(N-((2-Pyridinyl)methoxycarbonyl)valinyl)amino)-2-(N-diphenyl-3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 38 but replacing the resultant compoundof Example 3F with the resultant compound of Example 2D provided, aftersilica gel chromatography using a gradient of 2-5% methanol inchloroform, 102 mg (94%) of the desired compound (R_(f) 0.30, 10%methanol in chloroform) as a white solid, m.p. 172°-174° C. Massspectrum: (M+1)⁺ =654.

Anal. Calcd for C₃₇ H₄₃ N₅ O₆.0.5H₂ O: C, 67.05; H, 6.69; N, 10.51.Found: C, 66.70; H, 6.41; N, 10.37.

EXAMPLE 41 A. 2-(((N-Methyl)amino)methyl)thiazole

A mixture of 2.0 g (17.7 mmol) of the resultant compound of Example 14A,4.78 g (71 mmol) of methylamine hydrochloride, 4.36 g (53 mmol) ofsodium acetate and 1.67 g (27 mmol) of sodium cyanoborohydride in 50 mlof isopropyl alcohol was stirred at ambient temperature for 3 days. Theresulting mixture was concentrated in vacuo, and the residue was takenup in ethyl acetate and extracted with saturated aqueous NaHCO₃. Theaqueous layer was concentrated in vacuo to a small volume, saturatedwith NaCl, and extracted with 10% methanol in chloroform until noproduct remained in the aqueous layer by tlc. The combined organiclayers were dried over Na₂ SO₄ and concentrated in vacuo. Silica gelchromatography using first 5% then 10% methanol in chloroform provided0.4 g (18%) of the desired compound.

B. N-((N-Methyl-N-((2-thiazolyl)methyl)amino)carbonyl)valine MethylEster

A solution of 0.4 g (3.1 mmol) of the resultant compound of Example 41Aand 3.1 mmol of the resultant compound of Example 2A in 10 ml ofdichloromethane was stirred at ambient temperature for 1.5 h. Theresulting solution was concentrated in vacuo, and the residue waspurified by silica gel chromatography using first 1% then 2% methanol inchloroform to provide 0.57 g (64%) of the pure desired compound (R_(f)0.61, 10% methanol in chloroform).

C. N-((N-Methyl-N-((2-thiazolyl)methyl)amino)carbonyl)valine

A solution of 0.57 g (2.0 mmol) of the resultant compound of Example 41Bin 8 ml of dioxane was treated with 8 ml (4.0 mmol) of 0.5M aqueouslithium hydroxide. After being stirred at ambient temperature for 1 h,the resulting solution was neutralized with 1N aqueous HCl, concentratedin vacuo to a small volume, saturated with NaCl, and extracted with two100 ml portions of ethyl acetate. The combined organic layers were driedover Na₂ SO₄ and concentrated in vacuo to provide the desired compound.

D. N-((N-Methyl-N-((2-thiazolyl)methyl)amino)carbonyl)valinep-Nitrophenyl Ester

A solution of 2.0 mmol of the resultant compound of Example 41C and 0.3g (2.2 mmol) of 4-nitrophenol in 10 ml of tetrahydrofuran was treatedwith 0.43 g (2.2 mmol) of dicyclohexyl carbodiimide. After being stirredfor 3 h at ambient temperature, the mixture was filtered and the residuewas washed with 10 ml of fresh tetrahydrofuran. The combined filtrateswere concentrated in vacuo to provide the crude desired compound (R_(f)0.11, 20% ethyl acetate in chloroform).

E.(2S,3S,5S)-2-(N-(N-((N-Methyl-N-((2-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 37C but replacing the resultant compoundof Example 3F with the resultant compound of Example 41D provided thedesired compound.

EXAMPLE 42 A.(1S,2S)-2-((3-Pyridinyl)methoxycarbonyl)amino-1-cyclohexanol

A mixture of 21 mg (0.18 mmol) of (S,S)-2-aminocyclohexanol (Overman andSugai, et. al., J. Org. Chem. 1985, 50, 4154), 60 mg (0.22 mmol) of theresultant compound of Example 37A4 ml of tetrahydrofuran was heated atreflux for 1 h. The resulting mixture was concentrated in vacuo andpurified by silica gel chromatography using 4% methanol in chloroform toprovide 36 mg (79%) of the desired compound. ¹ H NMR (CDCl₃) δ 1.1-1.4(m, 4H), 1.7 (m, 2H), 1.82 (br s, 1H), 2.02 (m, 2H), 3.25-3.45 (m, 2H),4.98 (br, 1H), 5.12 (s, 2H), 7.29 (dd, J=7, 5 Hz, 1H), 7.70 (m, 1H),8.55 (dd, J=5, 2 Hz, 1H), 8.60 (d, J=2 Hz, 1H). Mass spectrum: (M+H)⁺=251.

B.(1'S,2'S)-(2-((3-Pyridinyl)methoxycarbonyl)amino-1-cyclohexyl)-4-nitrophenylcarbonate

A solution of 31 mg (0.12 mmol) of the resultant compound of 42A in 5 mlof dichloromethane was treated with 35 mg (0.18 mmol) of 4-nitrophenylchloroformate, stirred for 10 min, quenched with methanol andconcentrated in vacuo. Silica gel chromatography using first 20% ethylacetate in chloroform then 4% methanol in chloroform provided 48 mg(95%) of the desired compound. Mass spectrum: (M+H)⁺ =416.

C.(2S,3S,5S,1'S,2'S,1"S,2-S)-2,5-Bis-(N-(2-(N-((3-pyridinyl)methoxycarbonyl)amino-1-cyclohexyl)oxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

A solution of 48 mg (0.11 mmol) of the resultant compound of Example 42Band 16 mg (0.06 mmol) of the resultant compound of Example 1E in 15 mlof tetrahydrofuran was heated at reflux for 4 h. The resulting solutionwas concentrated in vacuo and purified by silica gel chromatographyusing 4% methanol in chloroform to provide 31 mg (75%) of the desiredcompound (R_(f) 0.12, 10% methanol in chloroform) as a foam whichsolidified. Mass spectrum: (M+1)⁺ =837.

EXAMPLE 43 A. 4-(((N-Methyl)amino)methyl)thiazole

Aqueous methylamine (100 ml, 40% by weight) was treated with 1.1 g (6.5mmol) of 4-(chloromethyl)thiazole hydrochloride. The resulting solutionwas stirred at ambient temperature for 15 min, concentrated in vacuo,taken up in 5% methanol in chloroform, dried over Na₂ SO₄, andconcentrated in vacuo to provide 0.81 g (97%) of the crude desiredcompound.

B. N-((N-Methyl-N-((4-thiazolyl)methyl)amino)carbonyl)valinep-Nitrophenyl Ester

Using sequentially the procedures of Examples 41B, 41C, and 41D, butreplacing the resultant compound of Example 41A with the resultantcompound of Example 43A provided the desired compound (R_(f) 0.17, 20%ethyl acetate in chloroform).

C.(2S,3S,5S)-2-(N-(N-((N-Methyl-N-((4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 37C but replacing the resultant compoundof Example 3F with the resultant compound of Example 43B provided, aftersilica gel chromatography using a gradient of 2-3-5% methanol inchloroform, a 49% of the desired compound (R_(f) 0.21, 10% methanol inchloroform) as a white solid. Mass spectrum: (M+1)⁺ =673. m.p. 71°-74°C.

Anal. Calcd for C₃₆ H₄₄ N₆ O₅ S.0.15CHCl₃ : C, 62.87; H, 6.42; N, 12.17.Found: C, 62.63; H, 6.19; N, 12.02.

EXAMPLE 44(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 38 but replacing the resultant compoundof Example 3F with the resultant compound of Example 43B provided, aftersilica gel chromatography using a gradient of 2-3-5% methanol inchloroform, a 43% of the desired compound (R_(f) 0.23, 10% methanol inchloroform) as a white solid. Mass spectrum: (M+1)⁺ =673. m.p. 69°-73°C.

Anal. Calcd for C₃₆ H₄₄ N₆ O₅ S.0.2CHCl₃ : C, 62.42; H, 6.37; N, 12.07.Found: C, 62.34; H, 6.11; N, 11.97.

EXAMPLE 45 A. 2-Amino-4-(((N-Methyl)amino)methyl)thiazole

Using the procedure of Example 43A but replacing4-(chloromethyl)thiazole hydrochloride with2-amino-4-(chloromethyl)thiazole dihydrochloride provided the crudedesired compound.

B. N-((N-Methyl-N-((2-amino-4-thiazolyl)methyl)amino)carbonyl)valineMethyl Ester

A solution of 4.26 g (27 mmol) of the resultant compound of Example 2Ain 100 ml of dichloromethane was added to 27 mmol of the crude resultantcompound of Example 45A followed by 3 ml (54 mmol) of4-methylmorpholine. The resulting mixture was stirred for 16 h atambient temperature, washed with saturated aqueous sodium bicarbonate,dried over Na₂ SO₄, and concentrated in vacuo to give the crude desiredcompound.

C.N-((N-Methyl-N-((2-((((t-butyl)oxy)carbonyl)amino)-4-thiazolyl)methyl)amino)carbonyl)valineMethyl Ester

A solution of 1.0 g (3.33 mmol) of the crude resultant compound ofExample 45B in 40 ml of dichloromethane was treated sequentially with0.87 g (4 mmol) of di-t-butyldicarbonate and 10 mg of4-dimethylaminopyridine. The resulting solution was stirred at ambienttemperature for 3 days, washed with 10% citric acid, dried over Na₂ SO₄,and concentrated in vacuo. Silica gel chromatography of the residueusing first 30% then 40% ethyl acetate in chloroform provided 0.65 g(49%) of the desired compound (R_(f) 0.58, 10% methanol in chloroform)as a foam.

D.N-((N-Methyl-N-((2-((((t-butyl)oxy)carbonyl)amino)-4-thiazolyl)methyl)amino)carbonyl)valineLithium Salt

A solution of 0.62 g (1.55 mmol) of the resultant compound of Example45C in 6.2 ml of dioxane was treated with 6.2 ml (3.1 mmol) of 0.5Maqueous lithium hydroxide. After being stirred for 2 h at ambienttemperature, the resulting solution was concentrated in vacuo to givethe crude desired compound.

E.(2S,3S,5S)-2-(N-(N-((N-Methyl-N-((2-((((t-butyl)oxy)carbonyl)amino)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

To a solution of 70 mg (0.17 mmol) of(2S,3S,5S)-2-amino-5-(N-((3-pyridinyl)methoxycarbonyl)-amino)-1,6-diphenyl-3-hydroxyhexane,0.20 mmol of the resultant compound of Example 45D, 34 mg (0.25 mmol) of1-hydroxybenzotriazole monohydrate and 37 μL (0.34 mmol) of4-methylmorpholine in 1 ml of tetrahydrofuran was added 48 mg (0.25mmol) of ethyl-(3-dimethylaminopropyl)-carbodiimide. The resultingsolution was stirred for 16 h at ambient temperature, diluted withchloroform, washed with saturated aqueous NaHCO₃, dried over Na₂ SO₄,and concentrated in vacuo. Silica gel chromatography using sequentially1.5% and 3% methanol in chloroform provided 97.2 mg (72.5%) of thedesired compound (R_(f) 0.59, 10% methanol in chloroform) as a whitesolid, m.p. 95°-98° C. Mass spectrum: (M+1)⁺ =788.

EXAMPLE 46(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-((((t-butyl)oxy)carbonyl)amino)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 45E but replacing(2S,3S,5S)-2-amino-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith(2S,3S,5S)-5-amino-2-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneprovided, after silica gel chromatography using a gradient of 1.5%-2%-3%methanol in chloroform, 96 mg (71.6%) of the desired compound (R_(f)0.60, 10% methanol in chloroform) as a white solid, m.p. 103°-105° C.Mass spectrum: (M+1)⁺ =788.

Anal. Calcd for C₄₁ H₅₃ N₇ O₇ S.0.75H₂ O: C, 61.44; H, 6.85; N, 12.23.Found: C, 61.16; H, 6.64, N, 11.91.

EXAMPLE 47 A.(2S,3R,4S,5S)-5-Amino-2-(N-(N-((N-methyl-N-((2-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane

A solution of 0.40 g (0.133 mmol) of the resultant compound of Example13D and 0.57 g (0.147 mmol) of the resultant compound of Example 3F in10 ml of tetrahydrofuran was stirred at ambient temperature for 16 h.The resulting solution was diluted with 50 ml of chloroform, washed withseveral portions of 3N aqueous NaOH, dried over Na₂ SO₄, andconcentrated in vacuo. Silica gel chromatography of the residue usingsequentially 3%, 5% and 10% methanol in chloroform provided 0.41 g (56%)of the desired compound (R_(f) 0.15, 10% methanol in chloroform).

B.(2S,3R,4S,5S)-2-(N-(N-((N-Methyl-N-((2-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane

A solution of 70 mg (0.13 mmol) of the resultant compound of Example 47Aand 42 mg (0.15-mmol) of the resultant compound of Example 37A in 1 mlof tetrahydrofuran was stirred at ambient temperature for 16 h. Theresulting solution was concentrated in vacuo, and the residue waspurified by silica gel chromatography using a gradient of 2%-3.5%methanol in chloroform to provide 72 mg (83%) of the desired compound(R_(f) 0.33, 10% methanol in chloroform) as a white solid, m.p. 86°-88°C. Mass spectrum: (M+1)⁺ =683.

Anal. Calcd for C₃₈ H₄₆ N₆ O₆.0.5H₂ O: C, 65.97; H, 6.85; N, 12.15.Found: C, 65.79; H, 6.53; N, 11.95.

EXAMPLE 48 A.(2S,3R,4S,5S)-5-Amino-2-(N-((3-pyridinyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane

A solution of 250 mg (0.83 mmol) of the resultant compound of Example13D and 251 mg (0.916 mmol) of the resultant compound of Example 37A in20 ml of tetrahydrofuran was stirred at ambient temperature for 16 h.The resulting solution was concentrated in vacuo, and the residue waspurified by silica gel chromatography using a gradient of 2%-3.5%-10%methanol in chloroform to provide 142 mg (57%) of the desired compound(R_(f) 0.15, 10% methanol in chloroform).

B.(2S,3R,4S,5S)-5-(N-(N-((N-Methyl-N-((2-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((3-pyridinyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane

A solution of 70 mg (0.13 mmol) of the resultant compound of Example 48Ain 1 ml of tetrahydrofuran was treated with 42 mg (0.15 mmol) of theresultant compound of Example 3F. The resulting solution was stirred atambient temperature for 16 h and concentrated in vacuo. The residued waspurified by silica gel chromatography using sequentially 2% and 3.5%methanol in chloroform to provide 66 mg (76%) of the desired compound(R_(f) 0.33, 10% methanol in chloroform) as a white solid, m.p. 82°-83°C. Mass spectrum: (M+1)⁺ =683.

Anal. Calcd for C₃₈ H₄₆ N₆ O₆.0.75H₂ O: C, 65.55; H, 6.88; N, 12.07.Found: C, 65.55; H, 6.49; N, 11.77.

EXAMPLE 49 A.(2S,3R,4S,5S)-5-Amino-2-(N-(N-((2-pyridinyl)methoxycarbonyl)valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane

Using the procedure of Example 47A but replacing the resultant compoundof Example 3F with the resultant compound of Example 2D provided, aftersilica gel chromatography using first 2% then 4% then 10% methanol inchloroform, 210 mg (24%) of the desired compound (R_(f) 0.20, 10%methanol in chloroform).

B.(2S,3R,4S,5S)-2-(N-(N-((2-Pyridinyl)methoxycarbonyl)valinyl)amino)-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane

Using the procedure of Example 47B but replacing the resultant compoundof Example 47A with the resultant compound of Example 49A provided,after silica gel chromatography using first 2% then 3.5% methanol inchloroform, 66 mg (75%) of the desired compound (R_(f) 0.32, 10%methanol in chloroform) as a white solid, m.p.166°-168° C. Massspectrum: (M+1)⁺ =670.

Anal. Calcd for C₃₇ H₄₃ N₅ O₇ : C, 66.35; H, 6.47; N, 10.46. Found: C,66.25; H, 6.53; N, 10.28.

EXAMPLE 50(2S,3R,4S,5S)-5-(N-(N-((2-Pyridinyl)methoxycarbonyl)valinyl)amino)-2-(N-((3-pyridinyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane

Using the procedure of Example 48B but replacing the resultant compoundof Example 3F with the resultant compound of Example 2D provided, aftersilica gel chromatography using first 2% then 4% then 10% methanol inchloroform, 61 mg (57%) of the desired compound (R_(f) 0.32, 10%methanol in chloroform) as a white solid, m.p.184°-185° C. Massspectrum: (M+1)⁺ =670.

Anal. Calcd for C₃₇ H₄₃ N₅ O₇.0.5H₂ O: C, 65.47; H, 6.53; N, 10.32.Found: C, 65.23; H, 6.27; N, 10.25.

EXAMPLE 51 A. 1-Amino-2-methyl-2-propanol Hydrochloride

A solution of 30 ml of borane-tetrahydrofuran (30 ml, 1M) was cooledunder N₂ atmosphere to 0° C. and treated in a dropwise fashion with muchgas evolution with 2 ml of acetone cyanohydrin. After addition, theresulting solution was heated at reflux for 4 h, allowed to cool,quenched cautiously (with gas evolution) with 100 ml of 1N aqueous HCl,and stirred for 1 h. The resulting mixture was washed four times withdichloromethane, then concentrated in vacuo to the desired compound anoil. The oil, when heated under high vacuum produced a white foam whichwas extremely hygroscopic.

B. 1-((3-Pyridinyl)methoxycarbonyl)amino-2-methyl-2-propanol

Using the procedure of Example 42A but replacingtrans-2-aminocyclohexanol hydrochloride with the resultant compound of51A provided, after silica gel chromatography using first 4% then 7.5%methanol in chloroform, the desired compound. ¹ H NMR (CDCl₃) δ 1.22 (s,6H), 3.20 (d, J=6 Hz, 2H), 5.13 (s, 2H), 5.18 (br, 1H), 7.30 (dd, J=7, 5Hz, I H), 7.71 (m, 1H), 8.58 (br d, J=5 Hz, 1H), 8.62 (br, 1H). Massspectrum: (M+H)⁺ =225.

C.1-((3-Pyridinyl)methoxycarbonyl)amino-2-methyl-2-propyl)-4-nitrophenylcarbonate

Using the procedure of Example 42B but replacing the resultant compoundof Example 42A with the resultant compound of Example 51B provided,after silica gel chromatography using first chloroform, then 3% methanolin chloform, the desired compound in 74% yield.

D.(2S,3S,5S)-2,5-Bis-(N-(N-(1-((3-pyridinyl)methoxycarbonyl)amino-2-methyl-2-propyl)oxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 42C but replacing the resultant compoundof Example 42B with the resultant compound of Example 51C provided,after silica gel chromatography using 5% methanol in chloroform, 80 mgthe desired compound (R_(f) 0.09, 5% methanol in chloroform). Massspectrum: (M+1)⁺ =785.

EXAMPLE 52 A. N-((3-Pyridinyl)methoxycarbonyl) valine p-Nitrophenyl

Using the procedures of Examples 2B, 2C and 2D but replacingpyridine-2-methanol with pyridine-3-methanol provided the desiredcompound.

B.(2S,3S,5S)-5-(N-(N-((3-Pyridinyl)methoxycarbonyl)valinyl)amino)-2-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 38 but replacing the resultant compoundof Example 3F with the resultant compound of Example 52A provided, aftersilica gel chromatography using a gradient of 2-3.5% methanol inchloroform, 81 mg (87%) of the desired compound (R_(f) 0.30, 10%methanol in chloroform) as a white solid. Mass spectrum: (M+1)⁺ =654.

EXAMPLE 53(2S,3S,5S)-2-(N-(N-((3-Pyridinyl)methoxycarbonyl)valinyl)amino)-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 37C but replacing the resultant compoundof Example 3F with the resultant compound of Example 52A provided, aftersilica gel chromatography using a gradient of 2-3.5% methanol inchloroform, 76 mg (81%) of the desired compound (R_(f) 0.30, 10%methanol in chloroform) as a while solid. Mass spectrum: (M+1)⁺ =654.

EXAMPLE 54

A. N-((2-Thiazolyl)methoxycarbonyl)valine p-Nitrophenyl Ester

Using the procedures of Examples 2B, 2C and 2D but replacingpyridine-2-methanol with 2-(hydroxymethyl)-thiazole (Dondoni, et. al.,Synthesis, 1987, 998; Tetrahedron Lett. 1983, 24, 2901) provided thedesired compound.

B. (2S,3S,5S) -5-(N-(N-((2-Thiazolyl)methoxycarbonyl)valinyl)amino)-2-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 38 but replacing the resultant compoundof Example 3F with the resultant compound of Example 54A provided, aftersilica gel chromatography using a gradient of 2-3.5% methanol inchloroform, 69 mg (86%) of the desired compound (R_(f) 0.36, 10%methanol in chloroform) as a white solid. Mass spectrum: (M+1)⁺ =660.

EXAMPLE 55

(2S,3S,5S)-2-(N-(N-((2-Thiazolyl)methoxycarbonyl)valinyl)amino)-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 37C but replacing the resultant compoundof Example 3F with the resultant compound of Example 54A provided, aftersilica gel chromatography using a gradient of 2-3.5% methanol inchloroform, a 90% of the desired compound (R_(f) 0.36, 10% methanol inchloroform) as a white solid. Mass spectrum: (M+1)⁺ =660.

EXAMPLE 56

A. 4-(Chloromethyl)-2-methylthiazole.

A mixture of 7.13 g (56 mmol) of 1,3-dichloroacetone, 3.83 g (51 mmol)of thioacetamide and 4.73 g (56 mmol) of NaHCO₃ in 40 ml ofdichloroethane was stirred at ambient temperature for four days. Theresulting mixture was filtered and the filter cake was washed with freshdichloroethane. The combined flit rates were added slowly to a precooled(0° C.) solution of 4.1 ml (56 mmol) of thionyl chloride in 30 ml ofdichloroethane. The resulting mixture was heated at 70° C. for 40 min,cooled, and filtered. The residue was washed with a small amount ofdichloromethane and dried under vacuum at 50° C. to provide 3.0 g of thecrude desired compound.

B. 4-((N-Methyl)aminomethyl)-2-methylthiazole.

The resultant compound of 56A (1.0 g) was added slowly in portions to100 ml of a rapidly stirred 40% aqueous solution of methylamine. Afterbeing stirred for 1 h, the solution was concentrated in vacuo, taken upin dichloromethane, dried over Na₂ SO₄, and concentrated to provide thecrude desired compound as a yellow oil.

C. N-((4-Nitrophenyloxy)carbonyl)valine Methyl Ester.

A solution of 1.36 g (6.8 mmol) of 4-(nitrophenyl) chloroformate in 50ml of dichloromethane was cooled to 0° C. and treated sequentially with1.03 g (6.1 mmol) of valine methyl ester hydrochloride and 1.42 ml (13mmol) of 4-methylmorpholine. The resulting solution was stirred atambient temperature for 1 h, diluted with dichloromethane, washed withaqueous NaHCO₃, dried over Na₂ SO₄, and concentrated to give the crudedesired compound.

D. N-((N-Methyl-N-((2-methyl-4-thiazolyl)methyl)amino)carbonyl)valineMethyl Ester.

A mixture of 5.4 mmol of the crude resultant compound of Example 56B and6.1 mmol of the crude resultant compound of Example 56C was treated with0.5 mmol of 4-dimethylpyridine in 40 ml of toluene and heated at refluxfor 4 h. The resulting solution was concentrated in vacuo, taken up indichloromethane, washed sequentially with aqueous NaHCO₃ and 10% citricacid, dried over Na₂ SO₄, and concentrated in vacuo. Silica gelchromatography using first chloroform, then 2%, then 5% methanol inchloroform provided 1.1 g of the desired compound.

E. N-((N-Methyl-N-((2-methyl-4-thiazolyl)methyl)amino)carbonyl)valinep-Nitrophenyl Ester.

Using the procedures of Examples 41C and 41D but replacing the resultantcompound of Example 41B with the resultant compound of Example 56Dprovided the desired compound.

F.(2S,3S,5S)-2-(N-(N-((N-Methyl-N-((2-methyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 37C but replacing the resultant compoundof Example 3F with the resultant compound of Example 56E provided, aftersilica gel chromatography using a gradient of 1.5-3-5% methanol inchloroform, a 72% of the desired compound (R_(f) 0.28, 10% methanol inchloroform) as a white solid. Mass spectrum: (M +1)⁺ =687. m.p. 66°-69°C.

EXAMPLE 57

(2S, 3S,5S)-2-(N-(N-((N-Methyl-N-((2-((((t-butyl)oxy)carbonyl)amino)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino-5-(N-(((t-butyl)oxy)carbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 45E but replacing(2S,3S,5S)-2-amino-5-(N-((3-pyridinyl)methoxycarbonyl)-amino-1,6-diphenyl-3-hydroxyhexane with(2S,3S,5S)-2-amino-5-(N-(((t-butyl)oxy)carbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneprovided 274 mg (93%) of the crude desired compound (R_(f) 0.43, 10%methanol in chloroform).

B.(2S,3S,5S)-5-Amino-2-(N-(N-((N-methyl-N-((2-amino-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 58B but replacing the resultant compoundof Example 58A with the resultant compound of Example 57A provided thedesired compound.

C.(2S,3S,5S)-2-(N-(N-((N-Methyl-N-((2-amino-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 47B but replacing the resultant compoundof Example 47A with the resultant compound of Example 57B provided,after silica gel chromatography using a gradient of 2%-3%-3.5%-5%-7%methanol in chloroform, 42 mg (50%) of the desired compound (R_(f) 0.22,10% methanol in chloroform). Mass spectrum: (M+1)⁺ =688.

EXAMPLE 58

A.(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-((((t-butyl)oxy)-carbonyl)amino)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-(((t=butyl)oxy)carbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 45E but replacing(2S,3S,5S)-2-amino-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith(2S,3S,5S)-5-amino-2-(N-(((t-butyl)oxy)carbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneprovided, after silica gel chromatography, 283 mg (96%) of the desiredcompound (R_(f) 0.43, 10% methanol in chloroform).

B.(2S,3S,5S)-2-Amino-5-(N-(N-((N-methyl-N-((2-amino-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-1,6-diphenyl-3-hydroxyhexane

A solution of 283 mg of the resultant compound of Example 58A in 10 mlof dichloromethane was treated with 5 ml of trifluoroacetic acid andstirred overnight at ambient temperature. The resulting solution wasconcentrated in vacuo, partitioned between saturated aqueous NaHCO₃ andchloroform, dried over Na₂ SO₄, and concentrated to provide the desired(R_(f) 0.49, 2% isopropylamine/5% methanol in chloroform).

C.(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-amino-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 47B but replacing the resultant compoundof Example 47A with the resultant compound of Example 58B provided,after silica gel chromatography using a gradient of 2%-3.5%-5% methanolin chloroform, 48 mg (58%) of the desired compound. Mass spectrum:(M+1)⁺ =688.

EXAMPLE 59

A. 2-(N-Ethylamino)methyl)pyridine.

Using the procedure of Example 70A but replacingquinoline-2-carboxaldehyde with pyridine-2-carboxaldehyde and replacingmethylamine with ethylamine provided the crude desired compound.

B. N-((N-Ethyl-N-((2-pyridinyl)methyl)amino)carbonyl)-valinep-Nitrophenyl Ester.

Using sequentially the procedures of Examples 41B, 41C, and 41D, butreplacing the resultant compound of Example 41A with the resultantcompound of Example 59A provided the desired compound.

C.(2S,3S,5S)-5-(N-(N-((N-Ethyl-N-((2-pyridinyl)-methyl)amino)carbonyl)valinyl)amino)-2-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 38 but replacing the resultant compoundof Example 3F with the resultant compound of Example 59B provided, aftersilica gel chromatography using a gradient of 2-5% methanol inchloroform, a 88% of the desired compound (R_(f) 0.28, 10% methanol inchloroform) as a white solid. Mass spectrum: (M+1)⁺ =861.

EXAMPLE 60

(2S,3S,5S)-2-(N-(N-((N-Ethyl-N-((2-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 37C but replacing the resultant compoundof Example 3F with the resultant compound of Example 59B provided, aftersilica gel chromatography using a gradient of 2-5% methanol inchloroform, a 93% of the desired compound (R_(f) 0.28, 10% methanol inchloroform) as a white solid. Mass spectrum: (M+1)⁺ =861

EXAMPLE 61

(2S,3R,4S,5S)-2-(N-(N-((N-methyl-N-((2-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-5-(N-(((t-butyl)oxy)carbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

A solution of 110 mg (0.20 mmol)of the resultant compound of Example 47Ain 1 ml of dichloromethane was treated with 53 mg (0.24 mmol) ofdi-t-butyldicarbonate. The resulting solution was stirred for 16 h atambient temperature, concentrated in vacuo, and purified by silica gelchromatography using first 1.5% then 2% methanol in chloroform toprovide 93 mg (72%) of the desired compound (R_(f) 0.53, 10% methanol inchloroform)as a white solid, m.p. 105°-107° C. Mass spectrum: (M+1)⁺=648

Anal. Calcd for C₃₆ H₄₉ N₅ O₆.0.25H₂ O: C, 66.29; H, 7.65; N, 10.74.Found: C, 66.11; H, 7.56; N, 10.64.

EXAMPLE 62

A.(2S,3R,4S,5S)-5-Amino-2-(N-(((t-butyl)oxy)carbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

A solution of 0.70 g (2.33 mmol)of the resultant compound of Example 13Dand 0.61 g (2.8 mmol) of di-t-butyldicarbonate in 20 ml ofdichloromethane was stirred at ambient temperature for 16 h. Theresulting solution was concentrated in vacuo, and the residue waspurified by silica gel chromatography using first 5% then 10% methanolin chloroform to provide 0.67 g (72%) of the desired compound (R_(f)0.32, 10% methanol in chloroform) as a white solid.

B.(2S,3R,4S,5S)-5-(N-(N-((N-Methyl-N-((2-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-(((t-butyl)oxy)carbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 48B but replacing the resultant compoundof Example 48A with the resultant compound of Example 62A provided,after silica gel chromatography using first 1.5% then 2% methanol inchloroform, 103 mg (79%) of the desired compound (R_(f) 0.55, 10%methanol in chloroform) as a white solid, m.p. 91°-93° C. Mass spectrum:(M+1)⁺ =648.

Anal. Calcd for C₃₆ H₄₉ N₅₀₆ : C, 66.75; H, 7.62; N, 10.81. Found: C,66.58; H, 7.34; N, 10.64.

EXAMPLE 63

A.(2S,3S,5S)-5-Amino-2-(N-(((t-butyl)oxy)-carbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneand(2S,3S,5S)-2-Amino-5-(N-(((t-butyl)oxy)carbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

A solution of 1.5 g (5.3 mmol) of the resultant compound of Example 1Eand 1.4 g (6.3 mmol) of di-t-butyldicarbonate in 50 ml ofdichloromethane was stirred at ambient temperature for 16 h. Theresulting solution was concentrated in vacuo, and the residue waspurified by silica gel chromatography using first 5% then 10% methanolin chloroform to provide a mixture of the desired compounds. A secondsilica column using sequentially 0%, 0.5%, and 1% methanol in 2%isopropylamine/chloroform provided 0.65 g of(2S,3S,5S)-5-amino-2-(N-(((t-butyl)oxy)carbonyl)amino)-1,6-diphenyl-3-hydroxyhexane(R_(f) 0.27) and 0.18 g of(2S,3S,5S)-2-amino-5-(N-(((t-butyl)oxy)carbonyl)amino)-1,6-diphenyl-3-hydroxyhexane(R_(f) 0.23, 2% methanol/2% isopropylamine in chloroform)along with 0.15g of a mixture or the two desired compounds.

B.(2S,3S,5S)-2-(N-(N-((N-Methyl-N-((2-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-5-(N-(((t-butyl)oxy)carbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 37C but replacing (2S,3S,5S)-2-amino-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith(2S,3S,5S)-2-amino-5-(N-(((t-butyl)oxy)carbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneprovided, after silica gel chromatography using 2% methanol inchloroform, 66 mg (92%) of the desired compound (R_(f) 0.60, 10%methanol in chloroform) as a white solid, m.p. 84°-85° C. Mass spectrum:(M+1)⁺ =632.

Anal. Calcd for C₃₆ H₄₉ N₅ O₅.0.5H₂ O: C, 67.48; H, 7.86; N, 10.93.Found: C, 67.40; H, 7.54; N, 10.90.

EXAMPLE 64

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-(((t-butyl)oxy)carbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 37C but replacing(2S,3S,5S)-2-amino-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith(2S,3S,5S)-5-amino-2-(N-(((t-butyl)oxy)carbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneprovided, after silica gel chromatography using 2% methanol inchloroform, 57 mg (80%) of the desired compound (R_(f) 0.60, 10%methanol in chloroform). Mass spectrum (M+1)⁺ =632.

EXAMPLE 65

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-methyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 38 but replacing the resultant compoundof Example 3F with the resultant compound of Example 56E provided, aftersilica gel chromatography using a gradient of 1-3-5% methanol inchloroform, a 82% of the desired compound (R_(f) 0.30, 10% methanol inchloroform) as a white solid. Mass spectrum: (M+1)⁺ =687. m.p. 69°-72°C.

EXAMPLE 66

A.(2S,3R,4S,5S)-5-(N-(N-((N-Methyl-N-((2-((((t-butyl)oxy)carbonyl)amino)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-((((t-butyl)oxy)-carbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 45E but replacing(2S,3S,5S)-2-amino-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith the resultant compound of Example 62A provided the desired compound(R_(f) 0.68, 10% methanol in chloroform).

B.(2S,3R,4S,5S)-2-Amino-5-(N-(N-((N-methyl-N-(2-amino-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 58B but replacing the resultant compoundof Example 58A with the resultant compound of Example 66A provided thedesired compound.

C.(2S,3R,4S,5S)-5-(N-(N-((N-Methyl-N-((2-amino-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(butyl)oxy)carbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 61 but replacing the resultant compoundof Example 47A with the resultant compound of Example 66B provided,after silica gel chromatography using first 2%, then 4%, then 6%methanol in chloroform, 61 mg (67%) of the desired compound (R_(f) 0.35,10% methanol in chloroform) as a white solid, m.p. 103°-107° C. Massspectrum: (M+1)⁺ =669.

EXAMPLE 67

(2S,3S,5S)-5-(N-(((t-Butyl)oxy)carbonyl)amino)-2-(N-(N-((N-methyl-N-((2-amino-4-thiazolyl)methyl)amino)-carbon)valinyl)amino)-1,6-diphenyl-3-hydroxyhexane.

A solution of 0.12 mmol of the resultant compound of Example 57B in 1 mlof dichloromethane was treated with 0.14 mmol of di-t-butyldicarbonate.After being stirred for three days at ambient temperature, the solutionwas concentrated in vacuo and purified by silica gel chromatographyusing a gradient of 2%-3.5%-5% methanol in chloroform to provide 48 mg(58%) of the desired compound (R_(f) 0.22, 10% methanol in chloroform).Mass spectrum: (M+1)⁺ =653.

EXAMPLE 68

(2S,3S,5S)-2-(N-(((t-Butyl)oxy)carbonyl)amino)-5-(N-(N-((N-methyl-N-((2-amino-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 67 but replacing the resultant compoundof Example 57B with the resultant compound of Example 58B provided,after silica gel chromatography using first 2% then 3.5% methanol inchloroform, 42 mg (54%) of the desired compound.

EXAMPLE 69

A 2-(((N-Methyl)amino)methyl)benzimidazole.

Using the procedure of Example 43A but replacing4-(chloromethyl)thiazole hydrochloride with2-(chloromethyl)benzimidazole hydrochloride provided the crude desiredcompound in 30% yield after silica gel chromatography using 2%isopropylamine/5% methanol in chloroform.

B. N-((N-Methyl-N-((2-benzimidazolyl)methyl)amino)carbonyl)valine MethylEster.

Using the procedure of Example 41B but replacing the resultant compoundof Example 41A with the resultant compound of Example 69A provided,after silica gel chromatography using 4% methanol in chloroform, 1.74 g(87%) of the desired compound (R_(f) 0.50, 4% methanol in chloroform).

C. N-((N-Methyl-N-((2-benzimidazolyl)methyl)amino)carbonyl)valine.

Using the procedure of Example 41C but replacing the resultant compoundof Example 41B with the resultant compound of Example 69B provided thedesired compound.

D. N-((N-Methyl-N-((2-benzimidazolyl)methyl)amino)carbonyl)valinep-Nitrophenyl Ester.

Using the procedure of Example 41D but replacing the resultant compoundof Example 41C with the resultant compound of Example 69C provided thedesired compound.

E.(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-benzimidazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 45E but replacing(2S,3S,5S)-2-amino-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith(2S,3S,5S)-5-amino-2-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneand replacing the resultant compound of Example 45D with the resultantcompound of Example 69C provided, after silica gel chromatography usingfirst 2.5% then 4.5% methanol in chloroform, 74.2 mg (62%) of thedesired compound (R_(f) 0.30, 10% methanol in chloroform)as a whitesolid, m.p. 97°-100° C. Mass spectrum: (M+1)⁺ =706.

Anal. Calcd for C₄₀ H₄₇ N₇ O₅.0.5H₂ O: C, 67.21; H, 6.77; N, 13.72.Found: C, 66.83; H, 6.70; N, 13.57.

EXAMPLE 70

A. 2- (N-Methylamino)methyl)quinoline.

A mixture of 1.93 g of quinoline-2-carboxaldehyde and 0.19 g of 10palladium on carbon in 15 ml of anhydrous methylamine and 45 ml ofmethanol was shaken under 4 atmospheres of hydrogen for 8 h. Theresulting mixture was filtered through Celite and concentrated in vacuoto provide the crude desired compound.

B. N-((N-Methyl-N-((2-quinolinyl)methyl)amino)carbonyl)valine

Using sequentially the procedures of Examples 41B and 41C, but replacingthe resultant compound of Example 41A with the resultant compound ofExample 70A provided the desired compound.

C.(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-quinolinyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((3,pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 46 but replacing the resultant compoundof Example 45D with the resultant compound of Example 70B provided,after silica gel chromatography using a gradient of 1-2.5% methanol inchloroform, 105 mg (60%) of the desired compound (R_(f) 0.40, 10%methanol in chloroform)as a white solid. Mass spectrum: (M+1)⁺ =717.

EXAMPLE 71

(2S,3S,5S)-2-(N-(N-((N-Methyl-N-((2-quinolinyl)methyl)amino)carbonyl)valinyl)amino)-5-(N-((3-pyridinyl)-methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 45E but replacing the resultant compoundof Example 45D with the resultant compound of Example 70B provided,after silica gel chromatography using a gradient of 1-2.5% methanol inchloroform, 100 mg (60%) of the desired compound (R_(f) 0.36, 10%methanol in chloroform)as a white solid. Mass spectrum: (M+1)⁺⁼ 717.

EXAMPLE 72

A. 1-(N-Methylamino)methyl)isoquinoline.

Using the procedure of Example 70A but replacingquinoline-2-carboxaldehyde with isoquinoline-1-carboxaldehyde (Minisci,et. al., J. Org. Chem., 1986, 51, 536) provided the crude desiredcompound.

B. N-((N-Methyl-N-(1-isoquinolinyl)methyl)amino)carbonyl)valinep-Nitrophenyl Ester.

Using sequentially the procedures of Examples 41B, 41C, and 41D, butreplacing the resultant compound of Example 41A with the resultantcompound of Example 72A provided the desired compound.

C.(2S,3S,5S)-5-(N-(N-((N-Methyl-N-(1-isoquinolinyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 38 but replacing the resultant compoundof Example 3F with the resultant compound of Example 72C provided, aftersilica gel chromatography using a gradient of 2-3.5% methanol inchloroform, 98 mg (96%) of the desired compound (R_(f) 0.41, 10%methanol in chloroform)as a white solid. Mass spectrum: (M+1)⁺ =717.

EXAMPLE 73

(2S,3S,5S)-2-(N-(N-((N-Methyl-N-((1-isoquinolinyl)methyl)amino)carbonyl)valinyl)amino)-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 37C but replacing the resultant compoundof Example 3F with the resultant compound of Example 72C provided, aftersilica gel chromatography using a gradient of 2-3.5% methanol inchloroform, 69 mg (67%)of the desired compound (R_(f) 0 41, 10% methanolin chloroform) as a white solid. Mass spectrum: (M+1 )⁺ =717.

EXAMPLE 74

(2S,3S,5S)-2-(N-(N-((N-Methyl-N-((2-benzimidazolyl)methyl)amino)carbonyl)valinyl)amino)-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 45E but replacing the resultant compoundof Example 45D with the resultant compound of Example 69C provided,after silica gel chromatography using first 2.5% then 4.5% methanol inchloroform, 74 mg (62%) of the desired compound (R_(f) 0.27, 10%methanol in chloroform)as a off-white solid, m.p. 110°-114° C. Massspectrum: (M+1)⁺ =706.

EXAMPLE 75

A. ((2-Thiazolyl)methyl)-(4-nitrophenyl)carbonate.

A solution 2.3 g (11.5 mmol) of (4-nitrophenyl)chloroformate in 20 ml ofdichloromethane was cooled to 0° C. and treated sequentially with asolution of 1.2 g (10.4 mmol) of 2- (hydroxymethyl)thiazole (Dondoni,et. al., Synthesis, 1987, 998; Tetrahedron Lett. 1983, 24, 2901)in 5 mlof dichloromethane and 1.7 ml (15.7 mmol) of 4-methylmorpholine. Afteraddition, the solution was allowed to come to ambient temperature,stirred for 0.5 h, and concentrated in vacuo. Silica gel chromatographyof the residue using first chloroform then 1% methanol in chloroformprovided 1.15 g (39%) of the desired compound (R_(f) 0.73, 10% methanolin chloroform).

B.(2S,3S,5S)-2,5-Bis-(N-((2-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

A solution of 130 mg (0.46 mmol) of the resultant compound of Example75A and 60 mg (0.21 mmol) of the resultant compound of Example 1E in 0.5ml of tetrahydrofuran was stirred at ambient temperature for 16 h. Theresulting solution was concentrated in vacuo, and the residue waspurified by silica gel chromatography using first 2% then 4% methanol inchloroform to provide 99 mg (83%) of the desired compound (R_(f) 0.73,10% methanol in chloroform) as a white solid, m.p. 66°-69° C. Massspectrum: (M+1)⁺ =567.

Anal. Calcd for C₂₈ H₃₆ N₄ O₅ S₂.0.5H₂ O: C, 58.42; H, 5.43; N, 9.73.Found: C, 58.23; H, 5.20; N, 9.61.

EXAMPLE 76

(2S,3R,4R,5S)-2,5-Bis-(N-((3-pyridinyl)methoxycarbonyl)amino)-3,4-dihydroxy- 1 6-diphenylhexane.

Using the procedure of Example 75B but replacing the resultant compoundof Example 75A with the resultant compound of Example 37A and replacingthe resultant compound of Example 1E with the resultant compound ofExample 4A provided, after silica gel chromatography using first 2% then3.5% methanol in chloroform, 280 mg of the desired compound (R_(f) 0.25,10% methanol in chloroform) as a white solid, m.p. 191°-193° C. Massspectrum: (M+1)⁺ =571.

Anal. Calcd for C₃₂ H₃₄ N₄ O₆ : C, 67.35; H, 6.01; N, 9.82. Found: C,67.11; H, 6.01; N, 9.64.

EXAMPLE 77

(2S,3R,4S,5S)-2,5-Bis-(N-((3-pyridinyl)methoxycarbonyl)amino)-3,4-dihydroxy-1.6-diphenylhexane.

Using the procedure of Example 75B but replacing the resultant compoundof Example 75A with the resultant compound of Example 37A and replacingthe resultant compound of Example 1E with the resultant compound ofExample 13D provided, after silica gel chromatography using first 2%then 3% methanol in chloroform, 110 mg of the desired compound (R_(f)0.42, 10% methanol in chloroform) as a white solid, m.p. 180°-186° C.Mass spectrum: (M+1)⁺ =571.

EXAMPLE 78

A. ((4-Thiazolyl)methyl)-(4-nitrophenyl)carbonate.

Using the procedure of Example 75A but replacing2-(hydroxymethyl)thiazole with 4-(hydroxymethyl)thiazole (Kollonitsch,U.S. Pat. No. 3,299,083) provided, after silica gel chromatography usingfirst chloroform then 1% methanol in chloroform, 380 mg (31%) of thedesired compound (R_(f) 0.70, 10% methanol in chloroform).

B.(2S,3S,5S)-2,5-Bis-(N-((4-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 75B but replacing the resultant compoundof Example 75A with the resultant compound of Example 78A provided,after silica gel chromatography using first 2% then 4% methanol inchloroform, 98.6 mg (83%) of the desired compound (R_(f) 0.43, 10%methanol in chloroform) as a white solid, m.p. 64°-66° C. Mass spectrum:(M+1)⁺ =567.

Anal. Calcd for C₂₈ H₃₆ N₄ O₅ S₂.0.5H₂ O: C, 58.42; H, 5.43; N, 9.73.Found: C, 58.45; H, 5.24; N, 9.61.

EXAMPLE 79

A. ((2-Methyl-5-thiazolyl)methyl)-(4-nitrophenyl)carbonate.

Using the procedure of Example 75A but replacing 2-(hydroxymethyl)thiazole with 2-methyl-5-(hydroxymethyl)thiazole (Mashraqui and Keehn,J. Am. Chem. Soc. 1982, 104, 4461) provided, after silica gelchromatography using 6% ethyl acetate in chloroform, 243 mg (65%) of thedesired compound (R_(f) 0.25, 10% methanol in chloroform).

B.(2S,3S,5S)-2,5-Bis-(N-((2-methyl-5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl)-3-hydroxyhexane.

Using the procedure of Example 75B but replacing the resultant compoundof Example 75A with the resultant compound of Example 79A provided,after silica gel chromatography using first 2% then 3% methanol inchloroform, 49 mg (29%) of the desired compound (R_(f) 0.5, 10% methanolin chloroform). Mass spectrum: (M+1)⁺ =595.

EXAMPLE 80

A. 5- (Carbethoxy)thiazole.

According to the procedure of Mashraqui and Keehn (J. Am. Chem. Soc.1982, 104, 4461), ethyl α-chloro-α-formylacetate was condensed withthioformamide and vacuum distilled to provide 5.65 g (33%) of thedesired compound.

B. 5, (Hydroxymethyl)thiazole

According to the procedure of Mashraqui and Keehn (J. Am. Chem. Soc.1982, 104, 4461), 5-(carbethoxy)thiazole was reduced with lithiumaluminum hydride to provide the crude desired compound in 44% yield.

C. ((5-Thiazolyl)methyl)-(4-nitrophenyl)carbonate

Using the procedure of Example 75A but replacing2-(hydroxymethyl)thiazole with 5-(hydroxymethyl)thiazole and allowingthe reaction to proceed at ambient temperature for 2 days provided,after silica gel chromatography using 6% ethyl acetate in chloroform,1.1 g (71%) of the desired compound (R_(f) 0.22, 6% ethyl acetate inchloroform). Mass spectrum: (M+1)⁺ =281.

D.(2S,3S,5S)-2,5-Bis-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 75B but replacing the resultant compoundof Example 75A with the resultant compound of Example 80C provided,after silica gel chromatography using first 2% then 3% methanol inchloroform, 145 mg (73%) of the desired compound (R_(f) 0.56, 10%methanol in chloroform). Mass spectrum: (M+1)⁺ =567.

EXAMPLE 81

A. N-((4-Methylpiperazin-1-yl)carbonyl)valine Methyl Ester.

Using the procedure of Example 41B but replacing the resultant compoundof Example 41A with 1-methylpiperazine provided, after silica gelchromatography using first 5% then 7.5% methanol in chloroform, 1.40 g(100%) of the desired compound (R_(f) 0.14, 5% methanol in chloroform).Mass spectrum: (M+1)⁺ =258.

B. N-((4-Methylpiperazin-1-yl)carbonyl)valine.

Using the procedure of Example 41C but replacing the resultant compoundof Example 41B with the resultant compound of Example 81A provided thedesired compound.

C.(2S,3R,4S,5S)-5-(N-(N-((4-Methylpiperazin-1-yl)carbonyl)valinylamino)-2-(N-(((t-butyl)oxy)carbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

To a solution of 70 mg (0.175 mmol) of the resultant compound of Example62A, 0.21 mmol of the resultant compound of Example 81B, 35 mg (0.26mmol) of 1-hydroxybenzotriazole monohydrate and 38 μL (0.35 mmol) of4-methylmorpholine in 1 ml of tetrahydrofuran was added 50 mg (0.26mmol) of ethyl(3-dimethylaminopropyl)-carbodiimide. The resultingsolution was stirred for 16 h at ambient temperature, diluted with 5%methanol in chloroform, washed with saturated aqueous NaHCO₃ andsaturated brine, dried over Na₂ SO₄, and concentrated in vacuo. Silicagel chromatography using sequentially 3%, 6% and 10% methanol inchloroform provided 82 mg (75%) of the desired compound (R_(f) 0.18, 10%methanol in chloroform). Mass spectrum: (M+H)⁺ =626.

Anal. Calcd for C₃₄ H₅₁ N₅ O₆. 0.5H₂ O: C, 64.33; H, 8.26; N, 11.03.Found: C, 64.05; H, 8.07; N, 11.07.

EXAMPLE 82

A.(2S,3S,4S,5S)-5-Amino-2-(N-(N-((2-pyridinyl)methoxycarbonyl)valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 47A but replacing the resultant compoundof Example 3F with the resultant compound of Example 2D and replacingthe resultant compound of Example 13D with the resultant compound ofExample 11C provided, after silica gel chromatography using first 5%then 10% methanol in chloroform, 340 mg (38%) of the desired compound(R_(f) 0.20, 10% methanol in chloroform).

B.(2S,3S,4S,5S)-2-(N-(N-((2-Pyridinyl)methoxycarbonyl)valinyl)amino)-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 47B but replacing the resultant compoundof Example 47A with the resultant compound of Example 82A provided,after silica gel chromatography using first 2% then 4% methanol inchloroform, 86.7 mg of the desired compound as a white solid, m.p.84°-85° C. Mass spectrum: (M+1)⁺ =670.

Anal. Calcd for C₃₇ H₄₃ N₅ O₆.1.0H₂ O: C, 64.61; H, 6.59; N, 10.18.Found: C, 64.46; H, 6.22; N, 10.04.

EXAMPLE 83

(2S,3S,4S,5S)-2,5-Bis-(N-((3-pyridinyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 75B but replacing the resultant compoundof Example 75A with the resultant compound of Example 37A and replacingthe resultant compound of Example 1E with the resultant compound ofExample 11C provided, after silica gel chromatography using first 2%then methanol in chloroform, 98.6 mg (74%) of the desired compound(R_(f) 0.45, 10% methanol in chloroform) as a white solid, m.p. 80°-82°C. Mass spectrum: (M+1)⁺ =571.

Anal. Calcd for C₃₂ H₃₄ N₄ O₆.0.5H₂ O: C, 66.31; H, 6.08; N, 9.67.Found: C, 66.09; H, 5.95; N, 9.53.

EXAMPLE 84

A.(2S,3R,4S,5S)-5-Amino-2-(N-(N-(((benzyl)oxy)carbonyl)valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 47A but replacing the resultant compoundof Example 3F with Cbz-valine p-nitrophenyl ester provided the desiredcompound.

B. (2S,3R,4S,5S)-5-(N-(N-((4-Methylpiperazin-1-yl)carbonyl)valinyl)amino)-2-(N-(N-(((benzyl)oxy)carbonyl)valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 81C but replacing the resultant compoundof Example 62A with the resultant compound of Example 84A provided,after silica gel chromatography using first 5% then 10% methanol inchloroform, 96.3 mg (71%) of the desired compound (R_(f) 0.11, 10%methanol in chloroform) as a white solid, m.p. 216°-219° C. Massspectrum: (M+1)⁺ =759.

Anal. Calcd for C₄₂ H₅₈ N₆ O₇.0.75H₂ O: C, 65.30; H, 7.76; N, 10.88.Found: C, 65.48; H, 7.49; N, 10.97.

EXAMPLE 85

(2S,3R,4R,5S)-2,5-Bis-(N-(N-((N-methyl-N-((4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

A solution of 75 mg (0.25 mmol) of the resultant compound of Example 43Band 0.75 mmol of the resultant compound of Example 4A in 1 ml oftetrahydrofuran was stirred at ambient temperature for 54 h. Theresulting solution was concentrated in vacuo. Silica gel chromatographyof the residue using first 2% then 5% methanol in chloroform, provided182 mg (91%) of the desired compound (R_(f) 0.33, 10% methanol inchloroform) as a white solid, m.p. 92°-94° C. Mass spectrum: (M+1)⁺=807.

Anal. Calcd for C₄₀ H₅₄ N₈ O₆ S₂.H₂ O: C, 58.23; H, 6.84; N, 13.58.Found: C, 57.87; H, 6.49; N, 13.40.

EXAMPLE 86

(2S,3S,4S,5S)-2,5-Bis-(N-(N-((N-methyl-N-((4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 3G but replacing the resultant compoundof Example 1E with the resultant compound of Example 11C and replacingthe resultant compound of Example 3F with the resultant compound ofExample 43B provided, after silica gel chromatography using first 2%then 5% methanol in chloroform, 179 mg (89%) of the desired compound(R_(f) 0.35, 10% methanol in chloroform) as a white solid, m.p. 94°-95°C. Mass spectrum: (M+1)⁺ =807.

Anal. Calcd for C₄₀ H₅₄ N₈ O₆ S₂.0.5H₂ O: C, 58.87; H, 6.79; N, 13.73.Found: C, 58.69; H, 6.52; N, 13.66.

EXAMPLE 87

(2S,3R,4S,5S)-2,5-Bis-(N-(N-((N-methyl-N-((4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 85 but replacing the resultant compoundof Example 4A with the resultant compound of Example 13D provided, aftersilica gel chromatography using first 2% then 5% methanol in chloroform,169 mg (85%) of the desired compound (R_(f) 0.31, 10% methanol inchloroform) as a white solid, m.p. 165°-167° C. Mass spectrum: (M+1)⁺=807.

Anal. Calcd for C₄₀ H₅₄ N₈ O₆ S₂.0.5H₂ O: C, 58.87; H, 6.79; N, 13.73.Found: C, 58.61; H, 6.57; N, 13.57.

EXAMPLE 88

(2S,3S,5S)-2,5-Bis-(N-(N-((N-methyl-N-((4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 85 but replacing the resultant compoundof Example 4A with the resultant compound of Example 1E provided, aftersilica gel chromatography using first 2% then 5% methanol in chloroform,151 mg (77%) of the desired compound (R_(f) 0.31, 10% methanol inchloroform) as a white solid, m.p. 154°-156° C. Mass spectrum: (M+1)⁺=791.

Anal. Calcd for C₄₀ H₅₄ N₈ O₅ S₂.0.25H₂ O: C, 60.39; H, 6.90; N, 14.09.Found: 60.30; H, 6.74; N, 13.96.

EXAMPLE 89

A. (2S,3S,4S,5S)-5.-Amino-2-(N-(N-((N-methyl-N-((2pyridinyl)methyl)amino)carbonyl)valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 47A but replacing the resultant compoundof Example 13D with the resultant compound of Example 11C provided,after silica gel chromatography using first 5% then 10% methanol inchloroform, 282 mg (40%) of the desired compound (R_(f) 0.14, 10%methanol in chloroform).

B.(2S,3S,4S,5S)-5-(N-(N-((N-Methyl-N-((4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-(N-((N-methyl-N-((2-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 38 but replacing the resultant compoundof Example 3F with the resultant compound of Example 43B and replacing(2S,3S,5S)-5-amino-2-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith the resultant compound of Example 89A provided, after silica gelchromatography using first 1.5% then 3% then 5% methanol in chloroform,73 mg (83%) of the desired compound (R_(f) 0.37, 10% methanol inchloroform) as a white solid, m.p. 84°-88° C. Mass spectrum: (M+1)⁺=801.

Anal. Calcd for C₄₂ H₅₆ N₈ O₆ S.0.5H₂ O: C, 62.28; H, 7.09; N, 13.83.Found: C, 62.03; H, 6.89; N, 13.64.

EXAMPLE 90

(2S,3S,4S,5S)-2-(N-(N-((N-Methyl-N-((2-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-5-(N-(N-((N-methyl-N-(pyridinyl)methyl)amino)carbonyl)valinyl)amino)-3,4-dihydroxy-1-diphenylhexane.

Using the procedure of Example 38 but replacing the resultant compoundof Example 3F with the resultant compound of Example 24F and replacing(2S,3S,5S)-5-amino-2-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith the resultant compound of Example 89A provided, after silica gelchromatography sequentially 2%, 4% and 6% methanol in chloroform, 64 mg(73%) of the desired compound (R_(f) 0.25, 10% methanol in chloroform)as a white solid, m.p. 92°-94° C. Mass spectrum: (M+1)⁺ =795.

EXAMPLE 91

(2S,3S,4S,5S)-2-(N-(N-((N-Methyl-N-((2-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-5-(N-(N-((4-methyl-piperazin-1-yl)carbonyl)valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 81C but replacing the resultant compoundof Example 62A with the resultant compound of Example 89A provided,after silica gel chromatography using sequentially 5% and 10% methanolin chloroform, 65 mg (62%) of the desired compound (R_(f) 0.15, 10%methanol in chloroform). Mass spectrum: (M+1)⁺ =773.

EXAMPLE 92

(2S,3S,4S,5S)-2,5-Bis-(N-(N-((N-methyl-N-((2-((((t-butyl)oxy)carbonyl)amino)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino-3,4-dihydroxy-1,6-diphenylhexane.

To a solution of 70 mg (0.23 mmol) of the resultant compound of Example11C, 0.5 2 mmol of the resultant compound of Example 45D, 94 mg (0.69mmol) of 1-hydroxybenzotriazole monohydrate and 50 μL (0.46 mmol) of4-methylmorpholine in 1 ml of dimethylformamide was added 130 mg (0.69mmol) of ethyl-(3-dimethylaminopropyl)-carbodiimide. The resultingsolution was stirred for 16 h at ambient temperature, diluted with ethylacetate, washed with saturated aqueous NaHCO₃, dried over Na₂ SO₄, andconcentrated in vacuo. Silica gel chromatography using sequentially 2%and 5% methanol in chloroform provided 210 mg (88%) of the desiredcompound (R_(f) 0.57, 10% methanol in chloroform) as a white solid, m.p.143°-145° C. Mass spectrum: (M+1)⁺ =1037.

EXAMPLE 93

(2S,3R,4S,5S)-2,5-Bis-(N-(N-((N-methyl-N-((2-((((t-butyl)oxy)carbonyl)amino)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-3,4-dihydroxy-1.6-diphenylhexane.

Using the procedure of Example 92 but replacing the resultant compoundof Example 11C with the resultant compound of Example 13D provided,after silica gel chromatography using 2% methanol in chloroform, 188 mg(80%) of the desired compound (R_(f) 0.5, 10% methanol in chloroform) asa white solid, m.p. 138°-140° C. Mass spectrum: (M+1)⁺ =1037.

(2S,3S,5S)-2,5-Bis-(N-(N-((N-methyl-N-((2-((((-butyl)oxy)carbonyl)amino)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 92 but replacing the resultant compoundof Example 11C with the resultant compound of Example 1E provided, aftersilica gel chromatography using 2% methanol in chloroform, 102 mg (43%)of the desired compound (R_(f) 0.57, 10% methanol in chloroform) as awhite solid, m.p. 115°-120° C. Mass spectrum: (M+1)⁺ =1021.

EXAMPLE 95

(2S,3S,4S,5S)-2,5-Bis-(N-(N-((N-methyl-N-((2-amino-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 58B but replacing the resultant compoundof Example 58A with the resultant compound of Example 92 provided, aftersilica gel chromatography using first 5% then 10% methanol inchloroform, 62 mg (43%) of the desired compound (R_(f) 0.16, 10%methanol in chloroform) as an off-white solid, m.p. 122°-124° C. Massspectrum: (M+1)⁺ =837.

Anal. Calcd for C₄₀ H₅₆ N₁₀ O₆ S₂.0.5CH₃ OH.0.5CHCl₃ : C, 53.98; H,6.41; H, 15.35. Found: C, 53.80; H, 6.36; N, 14.98.

EXAMPLE 96

(2S,3R,4S,5S)-2,5-Bis-(N-(N-((N-methyl-N-((2-amino-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 58B but replacing the resultant compoundof Example 58A with the resultant compound of Example 93 provided, aftersilica gel chromatography using first 5% then 10% methanol in chloroformfollowed by 2% isopropylamine/10% methanol in chloroform, 53 mg (38%) ofthe desired compound (R_(f) 0.15, 10% methanol in chloroform) as a whitesolid, m.p. 130°-134° C. Mass spectrum: (M+1)⁺ =837.

Anal. Calcd for C₄₀ H₅₆ N₁₀ O₆ S₂.2.25H₂ O: C, 54.74; H, 6.95; N, 15.96.Found: C, 54.74; H, 6.56; N, 15.57.

EXAMPLE 97

(2S,3S,5S)-2,5-Bis-(N-(N-((N-methyl-N-((2-amino-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 58B but replacing the resultant compoundof Example 58A with the resultant compound of Example 94 provided, aftersilica gel chromatography using first 5% then 10% methanol inchloroform, 52 mg (72%) of the desired compound (R_(f) 0.18, 10%methanol in chloroform) as a white solid, m.p. 110°-114° C. Massspectrum: (M+1)⁺ =821.

Anal. Calcd for C₄₀ H₅₆ N₁₀ O₆ S₂.0.5CH₃ OH.0.25CHCl₃ : C, 56.47; H,6.75; N, 16.16. Found: C, 56.85; H, 6.47; N, 15.45.

EXAMPLE 98

(2S,3S,4S,5S)-2-(N-(N-((N-Methyl-N-((2-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-5-(N-(N-((N-methyl-N-((2-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 38 but replacing the resultant compoundof Example 3F with the resultant compound of Example 41D and replacing(2S,3S,5S)-5-amino-2-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith the resultant compound of Example 89A provided, after silica gelchromatography using first 2% then 5% methanol in chloroform, 68 mg(78%) of the desired compound (R_(f) 0.34, 10% methanol in chloroform)as a white solid, m.p. 96°-97° C. Mass spectrum: (M+1)⁺ =801.

Anal. Calcd for C₄₂ H₅₆ N₈ O₆ S.0.5H₂ O: C, 62.28; H, 7.09; N, 13.83.Found: C, 62.35; H, 6.98; N, 13.67.

EXAMPLE 99

A.(2S,3S,4S,5S)-2-Amino-5-(N-(N-((N-methyl-N-((4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 47A but replacing the resultant compoundof Example 13D with the resultant compound of Example 11C and replacingthe resultant compound of Example 3F with the resultant compound ofExample 43B provided, after silica gel chromatography using first 2%then 10% methanol in chloroform, 113 mg (32%) of the desired compound(R_(f) 0.21, 10% methanol-in chloroform). Mass spectrum: (M+1)⁺ =669.

B.(2S,3S,4S,5S)-2-(N-(N-((N-Methyl-N-((2-((((t-butyl)oxy)carbonyl)amino)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-5-(N-(N-((N-methyl-N-((4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 45E but replacing(2S,3S,5S)-2-amino-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith the resultant compound of Example 99A provided the crude desiredcompound (R_(f) 0.71, 10% methanol in chloroform).

C.(2S,3S,4S,5S)-2-(N-(N-((N-Methyl-N-((2-amino-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-5-(N-(N-((N-methyl-N-((4-thiazolyl)methyl)amino)carbonyl)valinyl)-amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 58B but replacing the resultant compoundof Example 58A with the resultant compound of Example 99B provided,after silica gel chromatography using sequentially 2%, 4% and 6%methanol in chloroform, 61 mg (58%) of the desired compound (R_(f) 0.24,10% methanol in chloroform) as a white solid, m.p. 118°-120° C. Massspectrum: (M+1)⁺ =822.

Anal. Calcd for C₄₀ H₅₅ N₉ O₆ S₂.0.5CHCl₃ : C, 55.20; H, 6.29; N, 14.30.Found: C, 55.46; H, 5.91; N, 14.21.

EXAMPLE 100

(2S,3R,4R,5S)-2,5-Bis-(N-(N-((N-methyl-N-((2-benzimidazolyl)methyl)amino)carbonyl)valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 85 but replacing the resultant compoundof Example 43B with the resultant compound of Example 69D provided,after silica gel chromatography using 10% methanol in chloroform, 78 mg(40%) of the desired compound (R_(f) 0.18, 10% methanol in chloroform).Mass spectrum: (M+1)⁺ =873.

EXAMPLE 101

(2S,3S,4S,5S)-2,5-Bis-(N-(N-((N-methyl-N-((2-benzimidazolyl)methyl)amino)carbonyl)valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 85 but replacing the resultant compoundof Example 43B with the resultant compound of Example 69D and replacingthe resultant compound of Example 4A with the resultant compound ofExample 11C provided, after silica gel chromatography using 10% methanolin chloroform, 100 mg (50%) of the desired compound (R_(f) 0.15, 10%methanol in chloroform) as a white solid, m.p. 107°-109° C. Massspectrum: (M+1)⁺ =873.

EXAMPLE 102

(2S,3R,4S,5S)-2,5-Bis-(N-(N-((N-methyl-N-((2-benzimidazolyl)methyl)amino)carbonyl)valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 85 but replacing the resultant compoundof Example 43B with the resultant compound of Example 69D and replacingthe resultant compound of Example 4A with the resultant compound ofExample 13D provided, after silica gel chromatography using 10% methanolin chloroform, 100 mg (50%) of the desired compound (R_(f) 0.22, 10%methanol in chloroform) as a white solid, m.p. 145°-146° C. Massspectrum: (M+1)⁺ =873.

EXAMPLE 103

(2S,3S,5S)-2,5-Bis-(N-(N-((N-methyl-N-((2-benzimidazolyl)methyl)amino)carbonyl)valinyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 85 but replacing the resultant compoundof Example 43B with the resultant compound of Example 69D and replacingthe resultant compound of Example 4A with the resultant compound ofExample 1E provided, after silica gel chromatography using 6% methanolin chloroform, 130 mg (61%) of the desired compound (R_(f) 0.28, 10%methanol in chloroform) as a white solid, m.p. 150°-152° C. Massspectrum: (M+1)⁺ =857.

EXAMPLE 104

(2S,3R,4S,5S)-2,5-Bis-(N-(N-((4-methyl-piperazin-1-yl)carbonyl)valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 92 but replacing the resultant compoundof Example 11C with the resultant compound of Example 13D and replacingthe resultant compound of Example 45D with the resultant compound ofExample 81B provided, after silica gel chromatography using 10% methanolin chloroform followed by 2% isopropylamine/2% methanol in chloroform,74 mg (42%) of the desired compound (R_(f) 0.25, 2% isopropylamine/5%methanol in chloroform). Mass spectrum: (M+1)⁺ =751.

EXAMPLE 105

(2S,3S,4S,5S)-2-(N-(N-((N-Methyl-N-((4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-5-(N-(N-((4-methyl-piperazin-1-yl)carbonyl)valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 81C but replacing the resultant compoundof Example 62A with the resultant compound of Example 99A provided,after silica gel chromatography using sequentially 2%, 4% and 6%methanol in chloroform, 68 mg (69%) of the desired compound (R_(f) 0.24,10% methanol in chloroform). Mass spectrum: (M+1)⁺ =779.

EXAMPLE 106

(2S,3R,4S,5S)-2-(N-(N-((N-Methyl-N-((2-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-5-(N-(N-((N-methyl-N-((2-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 38 but replacing the resultant compoundof Example 3F with the resultant compound of Example 41D and replacing(2S,3S,5S)-5-amino-2-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith the resultant compound of Example 47A provided, after silica gelchromatography using sequentially 2%, 3.5% and 4% methanol inchloroform, 87 mg (85%) of the desired compound (R_(f) 0.33, 10%methanol in chloroform) as a white solid, m.p. 174°-176° C. Massspectrum: (M+1)⁺ =801.

Anal. Calcd for C₄₂ H₅₆ N₈ O₆ S: C, 62.98; H, 7.05; N, 13.99. Found: C,62.59; H, 6.99; N, 13.83.

EXAMPLE 107

A.(2S,3S,4S,5S)-2-(N-(N-((N-Methyl-N-((2-((((t-butyl)oxy)carbonyl)amino)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-5-(N-(N-((N-methyl-N-((2-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 45E but replacing(2S,3S,5S)-2-amino-5-(N-((3-pyridinyl)methoxycarbonyl)-amino)-1,6-diphenyl-3-hydroxyhexanewith the resultant compound of Example 89A provided the desired compound(R_(f) 0.65, 10% methanol in chloroform).

B.(2S,3S,4S,5S)-2-(N-(N-((N-Methyl-N-((2-amino-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-5-(N-(N-((N-methyl-N-(2-pyridinyl)methyl)amino)carbonyl)-valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 58B but replacing the resultant compoundof Example 58A with the resultant compound of Example 107A provided,after silica gel chromatography using sequentially 3%, 5% and 7%methanol in chloroform, 53 mg (35%) of the desired compound (R_(f) 0.21,10% methanol in chloroform) as a white solid, m.p. 97°-99° C.

Anal. Calcd for C₄₂ H₅₇ N₉ O₆ S.H₂ O: C, 60.48; H, 7.13; N, 15.11.Found: C, 60.25; H, 6.85; N, 14.84.

EXAMPLE 108

A. (2S,3S,4S,5S)-2-Amino-5-(N-(N-((N-methyl-N-((2-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 47A but replacing the resultant compoundof Example 13D with the resultant compound of Example 1! C and replacingthe resultant compound of Example 3F with the resultant compound ofExample 41D provided, after silica gel chromatography using first 5%then 10% methanol in chloroform, 248 mg (54%) of the desired compound(R_(f) 0.20, 10% methanol in chloroform).

B.(2S,3S,4S,5S)-2-(N-(N-((N-Methyl-N-((2-((((t-butyl)oxy)carbonyl)amine)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amine)-5-(N-(N-((N-methyl-N-((2-thiazolyl)methyl)amine)carbonyl)valinyl)amine)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 45E but replacing(2S,3S,5S)-2-amine-5-(N-((3-pyridinyl)methoxycarbonyl)-amino)-1,6-diphenyl-3-hydroxyhexanewith the resultant compound of Example 108A provided the desiredcompound (R_(f) 0.60, 10% methanol in chloroform).

C.(2S,3S,4S,5S)-2-(N-(N-((N-Methyl-N-((2-amino-4-thiazolyl)methyl)amine)carbonyl)valinyl)amine)-5-(N-(N-((N-methyl-N-((2-thiazolyl)methyl)amine)carbonyl)valinyl)-amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 58B but replacing the resultant compoundof Example 58A with the resultant compound of Example 108B provided,after silica gel chromatography using sequentially 3%, 5% and 7%methanol in chloroform, 69 mg (60%) of the desired compound (R_(f) 0.18,10% methanol in chloroform) as a white solid, m.p. 108°-111° C. Massspectrum: (M+1)⁺ =822.

Anal. Calcd for C₄₀ H₅₅ N₉ O₆ S₂.1.5H₂ O: C, 56.58; H, 6.88; N, 14.85.Found: C, 56.66; H, 6.51; N, 14.62.

EXAMPLE 109

A. (2S,3R,4S,5S)-2-Amino-5-(N-(N-((N-methyl-N-((2-pyridinyl)methyl)amine)carbonyl)valinyl)amine)-3,4,-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 58B but replacing the resultant compoundof Example 58A with the resultant compound of Example 62B provided,after silica gel chromatography using first 5% then 10% methanol inchloroform, a 67% yield of the desired compound (R_(f) 0.23, 10%methanol in chloroform).

B.(2S,3R,4S,5S)-2-(N-(N-((N-Methyl-N-((2-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-5-(N-(N-((N-methyl-N-((2-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 38 but replacing the resultant compoundof Example 3F with the resultant compound of Example 41D and replacing(2S,3S,5S)-5-amino-2-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith the resultant compound of Example 109A provided, after silica gelchromatography using sequentially 2%, 3.5% and 4% methanol inchloroform, 91 mg (79%) of the desired compound (R_(f) 0.32, 10%methanol in chloroform) as a white solid, m.p. 173°-175° C. Massspectrum: (M+1)⁺ =801.

Anal. Calcd for C₄₂ H₅₆ N₈ O₆ S.0.5H₂ O: C, 62.28; H, 7.09; N, 13.83.Found: C, 62.23; H, 7.00; N, 13.45.

EXAMPLE 110

A.(2S,3R,4S,5S)-5-(N-(N-((N-Methyl-N-((2-((((t-butyl)oxy)carbonyl)amino)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-(N-((N-methyl-N-((2-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 45E but replacing(2S,3S,5S)-2-amino-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith the resultant compound of Example 47A provided the desired compound(R_(f) 0.63, 10% methanol in chloroform).

B.(2S,3R,4S,5S)-5-(N-(N-((N-Methyl-N-((2-amino-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-(N-((N-methyl-N-((2-pyridinyl)methyl)amino)carbonyl)-valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 58B but replacing the resultant compoundof Example 58A with the resultant compound of Example 110A provided,after silica gel chromatography using sequentially 2%, 5% and 7%methanol in chloroform, 68 mg (57%) of the desired compound (R_(f) 0.28,10% methanol in chloroform).

EXAMPLE 111

A. N-((4-Morpholinyl)carbonyl)valine Methyl Ester.

Using the procedure of Example 41B but replacing the resultant compoundof Example 41A with morpholine provided a 91% yield of the desiredcompound. Mass spectrum: (M+1)⁺ =245.

B. N-((4-Morpholinyl)carbonyl)valine.

Using the procedure of Example 41C but replacing the resultant compoundof Example 41B with the resultant compound of Example IIIA provided thedesired compound in 98% yield.

C. N-((4-Morpholinyl)carbonyl)valine p-Nitrophenyl Ester.

Using the procedure of Example 41D but replacing the resultant compoundof Example 41C with the resultant compound of Example 111B provided thedesired compound.

D.(2S,3S,4S,5S)-5-(N-(N-((4-Morpholinyl)carbonyl)valinyl)amino)-2-(N-(N-((2-pyridinyl)methoxycarbonyl)valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 45E but replacing the resultant compoundof Example 45D with the resultant compound of Example 111B and replacing(2S,3S,5S)-2-amino-5-(N-((3-pyridinyl)methoxycarbonyl)-amino)-1,6-diphenyl-3-hydroxyhexanewith the resultant compound of Example 82A provided, after silica gelchromatography using sequentially 2% and 4% methanol in chloroform, 75mg (68%) of the desired compound (R_(f) 0.29, 10% methanol inchloroform). Mass spectrum: (M+1)⁺ =747.

Anal. Calcd for C₄₀ H₅₄ N₆ O₈.1.5H₂ O: C, 62.08; H, 7.42; N, 10.86.Found: C, 62.20; H, 7.16; N, 11.11.

EXAMPLE 112

A.(2S,3S,4S,5S)-5-(N-(N-((N-Methyl-N-((2-((((t-butyl)oxy)carbonyl)amino)-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-(N-((2-pyridinyl)methoxycarbonyl)valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 45E but replacing(2S,3S,5S)-2-amino-5-(N-((3-pyridinyl)methoxycarbonyl)-amino)-1,6-diphenyl-3-hydroxyhexanewith the resultant compound of Example 82A provided the desired compound(R_(f) 0.66, 10% methanol in chloroform).

B.(2S,3S,4S,5S)-5-(N-(N-((N-Methyl-N-((2-amino-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-(N-((2-pyridinyl)methoxycarbonyl)valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 58B but replacing the resultant compoundof Example 58A with the resultant compound of Example 112A provided,after silica gel chromatography using sequentially 2%, 5% and 7%methanol in chloroform, 60 mg (50%) of the desired compound (R_(f) 0.24,10% methanol in chloroform) as a white solid, m.p. 188°-192° C. Massspectrum: (M+1)⁺ =803.

Anal. Calcd for C₄₁ H₅₄ N₈ O₇ S.H₂ O: C, 59.98; H, 6.87; N, 13.65.Found: C, 60.27; H, 6.58; N, 13.48.

EXAMPLE 113

(2S,3S,5S)-2,5-Bis-(N-(N-((4-morpholinyl)carbonyl)valinyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 85 but replacing the resultant compoundof Example 4A with the resultant compound of Example 1E and replacingthe resultant compound of Example 43B with the resultant compound ofExample 111C provided, after silica gel chromatography using 5% methanolin chloroform, 62 mg (58%) of the desired compound (R_(f) 0.28, 10%methanol in chloroform) as a white solid, m.p. 198°-201° C. Massspectrum: (M+1)⁺ =709.

EXAMPLE 114

A.(2S,3S,5S)-5-Amino-2-(N-(N-((N-methyl-N-((2-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 58B but replacing the resultant compoundof Example 58A with the resultant compound of Example 63B provided thedesired compound (R_(f) 0.28, 2% isopropylamine/2% methanol inchloroform).

B.(2S,3S,5S)-5-(N-(N-(N-Methyl-N-((2-thiazolyl)methyl)amino)carbonyl)valinyl)-2-(N-(N-((N-methyl-N-((2-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 38 but replacing the resultant compoundof Example 3F with the resultant compound of Example 41D and replacing(2S,3S,5S)-5-amino-2-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith the resultant compound of Example 114A provided, after silica gelchromatography using first 2% then 4% methanol in chloroform, 75 mg(73%) of the desired compound (R_(f) 0.34, 10% methanol in chloroform)as a white solid, m.p. 158°-160° C. Mass spectrum: (M+1)⁺ =785.

Anal. Calcd for C₄₂ H₅₆ N₈ O₅ S: C, 64.26; H, 7.19; N, 14.27. Found: C,63.89; H, 7.14; N, 14.08.

EXAMPLE 115

A.(2S,3S,5S)-2-Amino-5-(N-(N-((N-methyl-N-((2-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 58B but replacing the resultant compoundof Example 58A with the resultant compound of Example 64 provided thedesired compound (R_(f) 0.20, 2% isopropylamine/2% methanol inchloroform).

B.(2S,3S,5S)-2-(N-(N-((N-Methyl-N-((2-thiazolyl)methyl)amino)carbonyl)valinyl)-5-(N-(N-((N-methyl-N-((2-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 38 but replacing the resultant compoundof Example 3F with the resultant compound of Example 41D and replacing(2S,3S,5S)-5-amino-2-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith the resultant compound of Example 115A provided, after silica gelchromatography using first 2% then 4% methanol in chloroform, 81 mg(78%) of the desired compound (R_(f) 0.33, 10% methanol in chloroform)as a white solid, m.p. 156°-158° C. Mass spectrum: (M+1)⁺ =785.

Anal. Calcd for C₄₂ H₅₆ N₈ O_(t) S: C, 64.26; H, 7.19; 14.27. Found: C,63.96; H, 6.99; N, 13.89.

EXAMPLE 116

A. Methyl-3-(1-Benzimidazolyl)propionate.

A solution of 10.0 g (84 mmol) of benzimidazole, 22.7 ml (250 mmol) ofmethyl acrylate and 3 drops of DBU in 50 ml of tetrahydrofuran washeated at reflux for 2 days. The resulting solution was concentrated invacuo, and the residue was purified by silica gel chromatography using3% methanol in chloroform to provide 15.7 g (92%) of the desiredcompound (R_(f) 0.58, 10% methanol in chloroform).

B. 3-(1-Benzimidazolyl)propionic Acid.

Using the procedure of Example 41C but replacing the resultant compoundof Example 41B with the resultant compound of Example 116A provided thedesired compound.

C.(2S,3R,4R,5S)-2,5-Bis-(N-(N-(3-(1-benzimidazolyl)propanoyl)valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 92 but replacing the resultant compoundof Example 45D with the resultant compound of Example 116B and replacingthe resultant compound of Example 11C with the resultant compound ofExample 4C provided, after silica gel chromatography using 10% methanolin chloroform, 216 mg (48%) of the desired compound (R_(f) 0.20, 10%methanol in chloroform). Mass spectrum: (M+1)⁺ =843.

EXAMPLE 117

A.(2S,3R,4R,5S)-5-Amino-2-(N-(((t-butyl)oxy)carbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 62A but replacing the resultant compoundof Example 13D with the resultant compound of Example 4A provided thedesired compound (R_(f) 0.58, 10% methanol in chloroform). Massspectrum: (M+1)⁺ =401.

B.(2S,3R,4R,5S)-5-(N-(N-((N-Methyl-N-((2-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-(((t-butyl)oxy)carbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 48B but replacing the resultant compoundof Example 48A with the resultant compound of Example 117A provided,after silica gel chromatography using first 1.5% then 2% methanol inchloroform, 101 mg (83%) of the desired compound (R_(f) 0.50, 10%methanol in chloroform) as a white solid. Mass spectrum: (M+1)⁺ =648.

EXAMPLE 118

(2S,3S,4S,5S)-2,5-Bis-(N-(N-((N-methyl-N-((3-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 85 but replacing the resultant compoundof Example 4A with the resultant compound of Example 11C and replacingthe resultant compound of Example 43B with the resultant compound ofExample 24F provided, after silica gel chromatography using 2%, then 5%,then 10% methanol in chloroform, 460 mg (58%) of the desired compound(R_(f) 0.17, 10% methanol in chloroform) as a white solid, m.p.174°-175° C. Mass spectrum: (M+1)⁺ =795.

Anal. Calcd for C₄₄ H₅₈ N₈ O₆.H₂ O: C, 65.00; H, 7.44; N, 13.78. Found:C, 65.09; H, 7.29; N, 13.61.

EXAMPLE 119

(2S,3R,4R,5S)-2,5-Bis-(N-(N-((N-methyl-N-((3-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 85 but replacing the resultant compoundof Example 43B with the resultant compound of Example 24F provided,after silica gel chromatography using first 5%, then 7.5%, then 10%methanol in chloroform, 249 mg (96%) of the desired compound (R_(f)0.31, 10% methanol in chloroform) as a white solid, m.p. 95°-97° C. Massspectrum: (M+1)⁺ =795.

Anal. Calcd for C₄₄ H₅₈ N₈ O₆.1.5H₂ O: C, 64.29; H, 7.48; N, 13.63.Found: C, 64.30; H, 7.20; N, 13.56.

EXAMPLE 120

(2S,3S,4S,5S)-2,5-Bis-(N-(N-((N-methyl-N-((2-pyridinyl)methyl)amino)carbonyl)isoleucinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 85 but replacing the resultant compoundof Example 4A with the resultant compound of Example 11C and replacingthe resultant compound of Example 43B with the resultant compound ofExample 16C provided, after silica gel chromatography using first 2%,then 3%, then 5% methanol in chloroform, 160 mg (59%) of the desiredcompound (R_(f) 0.38, 7.5% methanol in chloroform). Mass spectrum:(M+1)⁺ =823.

Anal. Calcd for C₄₆ H₆₂ N₈ O₆.H₂ O: C, 65.69; H, 7.67; N, 13.32. Found:C, 65.61; H, 7.49; N, 13.06.

EXAMPLE 121

(2S,3R,4S,5S)-2,5-Bis-(N-(N-((N-methyl-N-((2-pyridinyl)methyl)amino)carbonyl)isoleucinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 85 but replacing the resultant compoundof Example 4A with the resultant compound of Example 13D and replacingthe resultant compound of Example 43B with the resultant compound ofExample 16C provided, after silica gel chromatography using first 1%then 3% methanol in chloroform, 565 mg (67%) of the desired compound(R_(f) 0.37, 7.5% methanol in chloroform). Mass spectrum: (M+1)⁺ =823.

Anal. Calcd for C₄₆ H₆₂ N₈ O₆.0.25H₂ O: C, 66.76; H, 7.61; N, 13.54.Found: C, 66.56; H, 7.53; N, 13.45.

EXAMPLE 122

A. N-((N-Methyl-N-((2-pyridinyl)ethyl)amino)-carbonyl)valinep-Nitrophenyl Ester.

Using sequentially the procedures of Examples 41B, 41C, and 41D, butreplacing the resultant compound of Example 41A with2-((methylamino)ethyl)pyridine provided the desired compound.

B.(2S,3S,4S,5S)-2,5-Bis-(N-(N-((N-methyl-N-((2-pyridinyl)ethyl)amino)carbonyl)valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane,

Using the procedure of Example 85 but replacing the resultant compoundof Example 4A with the resultant compound of Example 11C and replacingthe resultant compound of Example 43B with the resultant compound ofExample 122A provided, after silica gel chromatography using first 2%then 5% methanol in chloroform, 170 mg (62%) of the desired compound(R_(f) 0.21, 7.5% methanol in chloroform) as a white solid, m.p.109°-111° C. Mass spectrum: (M+1)⁺ =823.

Anal. Calcd for C₄₆ H₆₂ N₈ O₆.0.5H₂ O: C, 66.40; H, 7.63; N, 13.47.Found: C, 66.17; H, 7.51; N, 13.41.

EXAMPLE 123

(2S,3R,4R,5S)-2,5-Bis-(N-(N-((N-methyl-N-((2-pyridinyl)ethyl)amino)carbonyl)valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 85 but replacing the resultant compoundof Example 43B with the resultant compound of Example 122A provided,after silica gel chromatography using first 7.5% then 10% methanol inchloroform, 220 mg (78%) of the desired compound (R_(f) 0.06, 7.5%methanol in chloroform). Mass spectrum: (M+1)⁺ =823.

Anal. Calcd for C₄₆ H₆₂ N₈ O₆.H₂ O: C, 65.69; H, 7.67; N, 13.32. Found:C, 65.64; H, 7.46; N, 13.26.

EXAMPLE 124

(2S,3R,4S,5S)-2,5-Bis-(N-(N-((N-methyl-N-((2-pyridinyl)ethyl)amino)carbonyl)valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 85 but replacing the resultant compoundof Example 4A with the resultant compound of Example 13D and replacingthe resultant compound of Example 43B with the resultant compound ofExample 122A provided, after silica gel chromatography using first 5%,then 7.5%, then 10% methanol in chloroform, 186 mg (65%) of the desiredcompound (R_(f) 0.23, 10% methanol in chloroform). Mass spectrum: (M+1)⁺=823.

EXAMPLE 125

(2S,3R,4S,5S)-2,5-Bis-(N-(N-((N-methyl-N-((3-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 85 but replacing the resultant compoundof Example 4A with the resultant compound of Example 13D and replacingthe resultant compound of Example 4 3B with the resultant compound ofExample 24F provided, after silica gel chromatography using sequentially2%, 7% and 10% methanol in chloroform, 189 mg (72%) of the desiredcompound (R_(f) 0.20, 10% methanol in chloroform) as a off-white solid,m.p. 174°-176° C. Mass spectrum: (M+1)⁺ =795.

Anal. Calcd for C₄₄ H₅₈ N₈ O₆.H₂ O: C, 65.00; H, 7.44; N, 13.78. Found:C, 65.18; H, 7.19; N, 13.68.

EXAMPLE 126

(2S,3S,5S)-2,5-Bis-(N-(N-((N-methyl-N-((3-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 85 but replacing the resultant compoundof Example 4A with the resultant compound of Example 1E and replacingthe resultant compound of Example 43B with the resultant compound ofExample 24F provided, after silica gel chromatography using first 2%,then 7%, then 10% methanol in chloroform, 132 mg (81%) of the desiredcompound (R_(f) 0.18, 10% methanol in chloroform) as a off-white solid,m.p. 193°-196° C. Mass spectrum: (M+1)⁺ =779.

Anal. Calcd for C₄₄ H₅₈ N₈ O₅.H₂ O: C, 66.31; H, 7.59; N, 14.06. Found:C, 66.22; H, 7.51; N, 13.59.

EXAMPLE 127

(2S,3R,4R,5S)-2,5-Bis-(N-(N-(3-(thiazol-2-yl)propanoyl)valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 92 but replacing the resultant compoundof Example 45D with the resultant compound of Example 34A and replacingthe resultant compound of Example 11C with the resultant compound ofExample 4C provided the desired compound.

EXAMPLE 128

(2S,4S)-24-Bis-(N-(N-(3-(thiazol-2-yl)propanoyl)valinyl)amino)-1,5-diphenyl-3-hydroxypentane.

Using the procedure of Example 92 but replacing the resultant compoundof Example 45D with the resultant compound of Example 34A and replacingthe resultant compound of Example 11C with the resultant compound ofExample 6H provided the desired compound.

EXAMPLE 123

(2S,3R,4R,5S)-2,5-Bis-(N-(N-((N-methyl-N-((2-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 85 but replacing the resultant compoundof Example 43B with the resultant compound of Example 41D provided,after silica gel chromatography using sequentially 1.5%, 2% and 5%methanol in chloroform, 140 mg (87%) of the desired compound (R_(f)0.27, 10% methanol in chloroform) as a white solid, m.p. 146°-148° C.Mass spectrum: (M+1)⁺ =807.

Anal. Calcd for C₄₀ H₅₄ N₈ O₆ S₂.0.5H₂ O: C, 58.87; H, 6.79; N, 13.73.Found: C, 58.57; H, 6.60; N, 13.47.

EXAMPLE 130

(2S,3S,4S,5S)-2,5-Bis-(N-(N-((N-methyl-N-((2-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 85 but replacing the resultant compoundof Example 4A with the resultant compound of Example 11C and replacingthe resultant compound of Example 43B with the resultant compound ofExample 41D provided, after silica gel chromatography using sequentially(1.5%, 2% and 5% methanol in chloroform, 138 mg (85.7%) of the desiredcompound (R_(f) 0.29, 10% methanol in chloroform) as a white solid, m.p.176°-178° C. Mass spectrum: (M+1)⁺ =807.

Anal. Calcd for C₄₀ H₅₄ N₈ O₆ S₂.0.5H₂ O: C, 58.87; H, 6.79; N, 13.73.Found: C, 58.77; H, 6.59; N, 13.61.

EXAMPLE 131

(2S,3R,4S,5S)-2,5-Bis-(N-(N-((N-methyl-N-((2-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 85 but replacing the resultant compoundof Example 4A with the resultant compound of Example 13D and replacingthe resultant compound of Example 43B with the resultant compound ofExample 41D provided, after silica gel chromatography using sequentially1.5%, 2% and 5% methanol in chloroform, 121.7 mg (75.4%) of the desiredcompound (R_(f) 0.27, 10% methanol in chloroform) as a white solid, m.p.198°-200° C. Mass spectrum: (M+1)⁺ =807.

Anal. Calcd for C₄₀ H₅₄ N₈ O₆ S₂ : C, 59.53; H, 6.74; N, 13.88. Found:C, 59.67; H, 6.66; N, 13.80.

EXAMPLE 132

(2S,3S,5S)-2,5-Bis-(N-(N-((N-methyl-N-((2-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 85 but replacing the resultant compoundof Example 4A with the resultant compound of Example 1E and replacingthe resultant compound of Example 43B with the resultant compound ofExample 41D provided, after silica gel chromatography using sequentially1.5%, 2% and 5% methanol in chloroform, 102 mg (64.6%) of the desiredcompound (R_(f) 0.30, 10% methanol in chloroform) as a white solid, m.p.195°-197° C. Mass spectrum: (M+1)⁺ =791.

Anal. Calcd for C₄₀ H₅₄ N₈ O₅ S₂.0.25H₂ O: C, 60.39; H, 6.90; N, 14.09.Found: 60.27; H, 6.79; N, 13.94.

EXAMPLE 133

A.(2S,3R,4R,5S)-5-Amino-2-(N-((3-pyridinyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 48A but replacing the resultant compoundof Example 13D with the resultant compound of Example 4A provided, aftersilica gel chromatography using sequentially 2%, 3.5%, 10% and 12%methanol in chloroform, 238 mg (41%) of the desired compound (R_(f)0.10, 10% methanol in chloroform). Mass spectrum: (M+1)⁺ =436.

B.(2S,3R,4R,5S)-2-(N-(N-((2-Pyridinyl)methoxycarbonyl)valinyl)amino)-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 38 but replacing the resultant compoundof Example 3F with the resultant compound of Example 2D and replacing(2S,3S,5S)-5-amino-2-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane with the resultant compound of Example 133Aprovided, after silica gel chromatography using first 2% then 3.5%methanol in chloroform, 62.1 mg (58%) of the desired compound (R_(f)0.32, 10% methanol in chloroform) as a white solid, m.p. 189°-190° C.Mass spectrum: (M+1)⁺ =770.

Anal. Calcd for C₃₇ H₄₃ N₅ O₇.0.25H₂ O: C, 65.91; H, 6.50; N, 10.39.Found: C, 65.91; H, 6.28; N, 10.36.

EXAMPLE 134

(2S,3S,4S,5S)-5-(N-(N-((N-Methyl-N-((2-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((3-pyridinyl)methoxycarbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane.

Using the procedure of Example 47B but replacing the resultant compoundof Example 47A with the resultant compound of Example 89A provided,after silica gel chromatography using first 2% then 3.5% methanol inchloroform, 74 mg (85%) of the desired compound (R_(f) 0.42, 10%methanol in chloroform) as a white solid, m.p. 84°-85° C. Mass spectrum:(M+1)⁺ =683.

Anal. Calcd for C₃₈ H₄₆ N₆ O₆.0.5H₂ O: C, 65.97; H, 6.85; N, 12.15.Found: C, 65.61; H, 6.73; N, 11.70.

EXAMPLE 135

A(2S,3S,5S)-2-Amino-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneand(2S,3S,5S)-5-Amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 37B but replacing the resultant compoundof Example 37A with the resultant compound of Example 80C provided,after silica gel chromatography using first 2% then 5% methanol inchloroform provided a mixture of the two desired compounds. Silica gelchromatography of the mixture using first 2% isopropylamine inchloroform followed by 2% isopropylamine/1% methanol in chloroform andfinally 2% isopropylamine/2% methanol in chloroform provided 111 mg(16%) of(2S,3S,5S)-2-amino-5-(N-((5-thiazolyl)-methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane and 185 mg (28%) of(2S,3S,5S)-2-amino-5-(N-((5-thiazolyl)-methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.Mass spectrum for each compound: (M+1)⁺ =426.

B.(2S,3S,5S)-2-(N-(N-((2-Pyridinyl)methoxycarbonyl)valinyl)amino)-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 37C but replacing(2S,3S,5S)-2-amino-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith (2S,3S,5S)-2-amino-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane and replacing the resultant compound ofExample 3F with the resultant compound of Example 2D provided, aftersilica gel chromatography using a gradient of 1%-3%-5% methanol inchloroform, 56 mg (72%) of the desired compound (R_(f) 0.50, 10%methanol in chloroform) as a white solid, m.p. 176°-177° C. Massspectrum: (M+1)⁺ =660.

Anal. Calcd for C₃₅ H₄₁ N₅ O₆ S.1.5H₂ O: C, 61.21; H, 6.46; N, 10.20.Found: C, 61.08; H, 6.00; N, 10.39.

EXAMPLE 136

(2S,3S,5S)-5-(N-(N-((2-Pyridinyl)methoxycarbonyl)valinyl)amino)-2- (N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 37C but replacing (2S,3S,5S)-2-amino-5-(N- ((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith(2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneand replacing the resultant compound of Example 3F with the resultantcompound of Example 2D provided, after silica gel chromatography using agradient of 1%-3%-5% methanol in chloroform, 48 mg (62% ) of the desiredcompound (R_(f) 0.47, 10% methanol in chloroform) as a white solid, m.p.176°-177° C. Mass spectrum: (M+1)⁺ =660.

EXAMPLE 137

(2S,3S,5S)-2-(N-(N-((N-Methyl-N-((2-pyridinyl)methyl)amino)carbonyl)isoleucinyl)amino)-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 37C but replacing(2S,3S,5S)-2-amino-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith(2S,3S,5S)-2-amino-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneand replacing the resultant compound of Example F with the resultantcompound of Example 16C provided, after silica gel chromatography usingfirst 2% then 5% methanol in chloroform, 51 mg (62%) of the desiredcompound (R_(f) 0.43, 10% methanol in chloroform) as a white solid, m.p.66°-69° C. Mass spectrum: (M+1)⁺ =687.

EXAMPLE 138

(2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-pyridinyl)methyl)amino)carbonyl)isoleucinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 37C but replacing(2S,3S,5S)-2-amino-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith(2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneand replacing the resultant compound of Example 3F with the resultantcompound of Example 16C provided, after silica gel chromatography usinga gradient of 2%-5% methanol in chloroform, 51 mg (62%) of the desiredcompound (R_(f) 0.47, 10% methanol in chloroform) as a white solid, m.p.64°-67° C. Mass spectrum: (M+1)⁺ =687.

EXAMPLE 139

(2S,3S,5S)-2-(N-(N-((N-Methyl-N-((2-amino-4-thiazolyl)methyl)amino)carbonyl)valinyl)amino)-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 47B but replacing the resultant compoundof Example 47A with the resultant compound of Example 57B and replacingthe resultant compound of Example 37A with the resultant compound ofExample 80C provided, after silica gel chromatography using a gradientof 2%-3%-5% methanol in chloroform, 46 mg (55%) of the desired compound(R_(f) 0.24, 10% methanol in chloroform). Mass spectrum: (M+1)⁺ =694.

EXAMPLE 140

(2S,4S)-2,4-Bis-(N-(N-(Boc-glycinyl)valinyl)amino)-1,5-diphenyl-3-hydroxypentane.

A solution of 100 mg (0.21 mmol) of the resultant compound of Example 6Hand 79.0 mg (0.94 mmol) of sodium bicarbonate in 2 ml of tetrahydrofuranand 2 ml of water was treated with a solution of 116.2 mg (0.43 mmol) ofN-t-Boc-glycine N-hydroxysuccinimide ester in 2 ml of tetrahydrofuran.After being stirred at ambient temperature for 2 h, the solution wasdiluted with dichloromethane, washed with water, dried over MgSO₄, andconcentrated in vacuo. Silica gel chromatography of the residue using10% methanol in dichloromethane provided 129.6 mg (78%) of the desiredcompound as a white solid. ¹ H NMR (DMSO-d₆) δ0.69-0.82 (m, 12H), 1.37(s, 18H), 1.73 (m, 1H), 1.94 (m, 1H), 2.45-2.62 (m, 2H), 2.73 (br d,2H), 2.97 (dd, 1H), 3.53 (m, 4H), 3.86 (m, 1H), 4.02 (m, 2H), 4.22 (m,1H), 5.29 (br d, 1H), 7.02-7.32 (m, 13H), 7.46-7.59 (m, 3H). Massspectrum: (M+H)⁺ =783.

EXAMPLE 141

(2S,4S)-2,4-Bis-(N-(N-(glycinyl)valinyl)amino)-1,5-diphenyl-3-hydroxypentane.

Using the procedure of Example 6F but replacing the resultant compoundof Example 6E with the resultant compound of Example 140 provided, aftersilica gel chromatography using 10% methanol in dichloromethane, 48.7 mg(91%) of the desired compound as a white solid. ¹ H NMR (DMSO-d₆)δ0.70-0.83 (four d, 12H), 1.78 (m, 1H), 1.96 (m, 1H), 2.62 (m, 2H), 2.74(br d, 2H), 2.97 (m, 1H), 3.46-3.87 (m, 5H), 4.02 (m, 2H), 4.21 (m, 1H),5.33 (br d, 1H), 7.08-7.26 (m, 10H), 7.57 (br d, 2H), 7.67 (br d, 1H),7.86 (br d, 1H). Mass spectrum: (M+H)⁺ =583.

EXAMPLE 142

(2S,4S)-2,4-Bis-(N-(N-((4-pyridinylthio)acetyl)valinyl)amino)-1,5-diphenyl-3-hydroxypentane.

A.(2S,4S)-2,4-Bis-(N-(N-(bromoacetyl)valinyl)amino)-1,5-diphenyl-3-hydroxypentane.

A solution of 100 mg (0.21 mmol) of the resultant compound of Example 6Hand 34.5 μl (0.43 mmol) of pyridine in 10 ml of dichloromethane wastreated with 37.2 μl (0.43 mmol) of bromoacetyl bromide at 0° C. Afterbeing stirred at 0° C. for 1 h, the solution was diluted withdichloromethane, washed with water, dried over MgSO₄, and concentratedin vacuo. Silica gel chromatography of the residue using 10% methanol indichloromethane provided 108.3 mg (71%) of the desired compound as awhite solid. Mass spectrum: (M+H)⁺ =709.

B.(2S,4S)-2,4-Bis-(N-(N-((4-pyridinylthio)acetyl)valinyl)amino)-1,5-diphenyl-3-hydroxypentane

A solution of 50.0 mg (0.070 mmol) of the resultant compound of Example142A and 18.4 μl (0.14 mmol) of triethylamine in 2 ml ofdimethylformamide was treated with 15.6 mg (0.14 mmol) of4-mercaptopyridine. After being stirred at ambient temperature for 2 h,the solution was diluted with dichloromethane, washed with water, driedover MgSO₄, and concentrated in vacuo. Silica gel chromatography of theresidue using 10% methanol in dichloromethane provided 57.2 mg (73%) ofthe desired compound as a pale yellow solid. ¹ H NMR (CDCl₃) δ0.72 (t,6H), 0.79 (t, 6H), 1.74 (m, 1H), 1.93 (m, 1H), 2.56 (m, 2H), 2.76 (br d,2H), 2.93 (m, 1H), 3.70-3.95 (m, 5H), 4.03 (m, 2H), 4.23 (dd, 1H), 5.32(d, 1H), 7.04-7.25 (m, 10H), 7.31 (m, 4H), 7.54 (br d, 1H), 7.62 (br d,1H), 8.02 (br d, 1H), 8.18 (br d, 1H), 8.34 (m, 4H). Mass spectrum:(M+H)⁺ =771.

EXAMPLE 143

(2S,4S)-2,4-Bis-(N-(N-((2-pyridinylthio)acetyl)valinyl)amino)-1,5-diphenyl-3-hydroxypentane.

Using the procedure of Example 142B but replacing 4-mercaptopyridinewith 2-mercaptopyridine provided 32.3 mg (85%) of the desired compoundas a white solid. ¹ H NMR (DMSO-d6) δ0.62 (d, 3H), 0.68 (two d, 6H),0.76 (d, 3H), 1.73 (m, 1H), 1.92 (m, 1H), 2.58 (dd, 2H), 2.70 (br d,2H), 2.96 (dd, 1H), 3.73-3.96 (m, 5H), 4.01 (m, 2H), 4.18 (dd, 1H), 5.29(d, 1H), 7.04-7.23 (m, 12H), 7.36 (dd, 2H), 7.49 (br d, 1H), 7.56 (br d,1H), 7.64 (td, 2H), 7.83 (br d, 1H), 8.00 (br d, 1H), 8.38 (tt, 2H).Mass spectrum: (M+H)⁺ =771.

EXAMPLE 144

(2S,4S)-2,4-Bis-(N-(N-(N-(acetyl)glycinyl)valinyl)amino)-1,5-diphenyl-3-hydroxypentane.

A solution of 200 mg (0.34 mmol) of the resultant compound ofExample.141 and 98.4 μl (0.75 mmol) of triethylamine in 4 ml ofdimethylformamide was treated with 68.0 μl (0.72 mmol) of aceticanhydride. After being stirred at ambient temperature for 2 h, thesolution was diluted with water and extracted with four 10 ml portionsof 10% methanol in dichloromethane. The combined organic layers weredried over MgSO₄, and concentrated in vacuo. Silica gel chromatographyof the residue using 10% methanol in dichloromethane provided 164.1 mg(72%) of the desired compound as a white solid. ¹ H NMR (DMSO-d₆)δ0.69-0.81 (four d, 12H), 1.76 (m, 1H), 1.84 (two s, 6H), 1.92 (m, 1H),2.60 (dd, 2H), 2.74 (br d, 2H), 2.97 (dd, 1H), 3.67 (d, 2H), 3.72 (d,2H), 3.85 (m, 1H), 4.02 (m, 2H), 4.17 (dd, 1H), 5.24 (d, 1H), 7.07-7.26(m, 10H), 7.46(br d, 1H), 7.53 (br d, 1H), 7.56 (br d, 1H), 7.72(br d,1H), 8.07 (br t, 1H), 8.12 (br t, 1H). Mass spectrum: (M+H)⁺ =667.

EXAMPLE 145

(2S,4S)-2,4-Bis-(N-(N-(N-((2-pyridinyl)methoxycarbonyl)glycinyl)valinyl)amino)-1,5-diphenyl-3-hydroxypentane.

A. N-((2-pyridinyl)methoxycarbonyl)glycine Methyl Ester.

Using the procedure of Example 2B but replacing the resultant compoundof Example 2A with isocyanato-glycine methyl ester provided the desiredcompound.

B. N-((2-pyridinyl)methoxycarbonyl)glycine.

Using the procedure of Example 3E but replacing the resultant compoundof Example 3D with the resultant compound of Example 145A provided thedesired compound.

C.(2S,4S)-2,4-Bis-(N-(N-(N-((2-pyridinyl)methoxycarbonyl)glycinyl)valinyl)amino)-1,5-diphenyl-3-hydroxypentane.

Using the procedure of Example 6I but replacingtrans-3-(pyridinyl)acrylic acid with the resultant compound of Example142B provided 289.6 mg (80%) of the desired compound as a white solid. ¹H NMR (DMSO-d6) δ0.63-0.75 (four d, 12H), 1.66 (m, 1H), 1.84 (m, 1H),2.49 (m, 2H), 2.64 (m, 2H), 2.90 (m, 1H), 3.55 (m, 2H), 3.59 (d, 2H),3.78 (m, 1H), 3.94 (m, 2H), 4.14 (dd, 1H), 5.00 (s, 4H), 5.19 (d, 1H),6.98-7.23 (m, 12H), 7.29 (d, 2H), 7.42 (br d, 2H), 7.51 (m, 3H), 7.58(d, 1H), 7.73 (br t, 1H), 8.44 (d, 2H). Mass spectrum: (M+H)⁺ =853.

EXAMPLE 146

(2S,4S)-2,4-Bis-(N-(N-(N-(3-(Cbz-amino)-3-methylbutyryl)glycinyl)valinyl)amino)-1,5-diphenyl-3-hydroxypentane.

Using the procedure of Example 6I but replacingtrans-3-(pyridinyl)acrylic acid withN-(3-(Cbz-amino)-3-methylbutyryl)glycine provided 261.2 mg (86%) of thedesired compound as a white solid. ¹ H NMR (CDCl₃) δ0.66 (d, 3H), 0.69(d, 3H), 0.75 (d, 3H), 0.77 (d, 3H), 1.34-1.42 (four s, 12H), 1.72 (m,1H), 1.96 (m, 1H), 2.46-2.65 (m, 4H), 2.81 (m, 1H), 3.04-3.12 (m, 2H),3.27 (dd, 1H), 3.47 (d, 2H), 3.55-3.69 (m, 4H), 3.89 (m, 2H), 4.37 (m,1H), 4.69 (d, 1H), 5.03 (s, 4H), 5.35 (br, 1H), 5.73 (br, 1H), 6.48 (brd, 1H), 6.55 (br d, 1H), 6.70 (br, 1H), 6.84 (br d, 1H), 7.02 (br d,2H), 7.10-7.38 (m, 20H). Mass spectrum: (M+H)⁺ =1049.

EXAMPLE 147

(2S,4S)-2,4-Bis-(N-(N-(N-(methoxycarbonyl)glycinyl)valinyl)amino)-1,5-diphenyl-3-hydroxypentane.

Using the procedure of Example 144 but replacing acetic anhydride withmethyl chloroformate provided 77.0 mg (43%) of the desired compound as awhite solid. Mass spectrum: (M+H)⁺ =699.

EXAMPLE 148

(2S,4S)-2,4-Bis-(N-(N-(N-(3-amino-3-methylbutyryl)glycinyl)valinyl)amino)-1,5-diphenyl-3-hydroxypentane.

Using the procedure of Example 6H but replacing the resultant compoundof Example 6G with the resultant compound of Example 146 provided 127.0mg (95%) of the desired compound as a white solid. ¹ H NMR (CDCl₃) δ0.73(t, 6H), 0.87 (d, 6H), 1.23 (s, 6H), 1.24 (s, 3H), 1.26 (s, 3H), 1.61(br s, 5H), 1.96 (m, 1H), 2.17-2.31 (m, 4H), 2.89 (m, 1H), 3.07 (m, 2H),3.27 (m, 1H), 3.53 (m, 1H), 3.58 (m, 1H), 3.70-3.77 (m, 6H), 4.04-4.1 8(m, 2H), 6.56 (br d, 1H), 6.94 (br d, 1H), 7.14-7.26 (m, 10H), 7.46 (brd, 1H), 7 . 83 (br d, 1H), 8.34 (m, 2H). Mass spectrum: (M+H)⁺ =781 .

EXAMPLE 149

(2S,4S)-2,4-Bis-(N-(N-(N-(3-pyridinyl)glycinyl)valinyl)amino)-1,5-diphenyl-3-hydroxypentane.

Using the procedure of Example 6I but replacingtrans-3(pyridinyl)acrylic acid with N-(3-pyridinyl)glycine provided 94.2mg (80%) of the desired compound as a pale yellow solid. ¹ H NMR(DMSO-d6) δ0.63 (d, 3H), 0.70 (d, 6H), 0.77 (d, 3H, 1.73 (m, 1H), 1.92(m, 1H), 2.56 (m, 2H), 2.71 (d, 2H), 2.97 (dd, 1H), 3.55-3.87 (m, 5H),4.03 (m, 2H), 4.24 (dd, 1H), 5.36 (d, 1H), 6.22 (two d, 2H), 6.86 (m,2H), 7.04-7.23 (m, 12H), 7.52-7.59 (m, 3H), 7.74 (br d, 1H), 7.78 (m,2H), 7.96 (m, 2H). Mass spectrum: (M+H)⁺ =737.

EXAMPLE 150

(2S,4S)-2,4-Bis-(N-(N-(N-(2-pyridinyl)glycinyl)valinyl)amino-1,5-diphenyl-3-hydroxypentane.

Using the procedure of Example 6I but replacingtrans-3-(pyridinyl)acrylic acid with N-(2-pyridinyl)glycine provided119.9 mg (76%) of the desired compound as a pale yellow solid. ¹ H NMR(DMSO-d6) δ0.58 (d, 3H), 0.65 (d, 3H), 0.69 (d, 3H), 0.76 (d, 3H), 1.73(m, 1H), 1.92 (m, 1H), 2.57 (dd, 2H), 2.70 (dd, 2H), 2.96 (dd, 1H),3.78-3.85 (m, 5H), 4.00 (m, 2H), 4.22 (dd, 1H), 5.29 (d, 1H), 6.49-6.58(m, 4H), 6.78 (m, 2H), 7.04-7.23 (m, 10H), 7.32-7.41 (m, 3H), 7.48 (brd, 1H), 7.53 (br d, 2H), 7.94 (m, 2H). Mass spectrum: (M+H)⁺ =737.

EXAMPLE 151

(2S,4S)-2,4-Bis-(N-(N-(N-(3,3-dimethylbutyl)glycinyl)valinyl)amino)-1,5-diphenyl-3-hydroxypentane.

A solution of 200.0 mg (0.28 mmol) of the resultant compound of Example142A in 5 ml of dimethylformamide was treated with 152 μl (1.13 mmol) of3,3-dimethylbutylamine. After being stirred at ambient temperature for 2h, the solution was diluted with chloroform, washed with water, driedover MgSO₄, and concentrated in vacuo. Silica gel chromatography of theresidue using 10% methanol in dichloromethane provided 155.5 mg (74%) ofthe desired compound as a white solid. ¹ H NMR (DMSO-d6) δ0.71-0.83(four d, 12H), 0.85 (s, 18H), 1.33 (m, 4H), 1.78 (m, 1H), 1.98 (m, 1H),2.43 (m, 4H), 2.58 (m, 2H), 2.73 (m, 2 H), 2.96-3.12 (m, 5H), 3.86 (m,1H), 4.04 (m, 2H), 4.27 (dd, 1H), 5.33 (d, 1H), 7.06-7.24 (m, 10H), 7.58(br d, 2H), 7.64 (br d, 1H), 7.81 (br d, 1H). Mass spectrum: (M+H)⁺=751.

EXAMPLE 152

(2S,4S)-2,4-Bis-(N-(N-(N-(2-methoxyethyl)glycinyl)valinyl)amino)-1,5-diphenyl-3-hydroxypentane.

Using the procedure of Example 151 but replacing 3,3-dimethylbutylaminewith 2-methoxyethylamine provided 150.5 mg (77%) of the desired compoundas a white solid. ¹ H NMR (CDCl₃)8 0.76 (d, 3H), 0.79 (d, 3H), 0.90 (d,3H), 0.93 (d, 3H), 2.03 (m, 1H), 2.26 (m, 1H), 2.57-2.78 (m, 4H),2.88-3.38 (m, 10H), 3.33 (s, 3H), 3.36 (s, 3H), 3.47 (t, 2H), 3.57 (m,2H), 3.78 (dd, 1H), 3.84 (t, 1H), 4.11 (t, 1H), 6.76 (br d, 1H),7.14-7.28 (m, 12H), 7.42 (br d, 1H), 7.72 (br d, 1H), 7.77 (br d, 1H).Mass spectrum: (M+H)+=6 99.

EXAMPLE 153

(2S,4S)-2,4-Bis-(N-(N-(Cbz-alaninyl)valinyl)amino)-1,5-diphenyl-3-hydroxypentane.

Using the procedure of Example 6I but replacingtrans-3(pyridinyl)acrylic acid with Cbz-D-alanine provided 171.1 mg(91%) of the desired compound as a white solid. Mass spectrum: (M+H)⁺=879.

EXAMPLE 154

(2S,3R,4S)-2,4-Bis-(N-(N-((2-pyridinyl)methoxycarbonyl)valinyl)amino)-5-(3,5-dimethylphenyl)-3-hydroxy-1-phenylpentane.

A.(2S,3R,4R)-2-(Cbz-amino)-3,4-dihydroxy-5-(3,5-dimethylphenyl)-1-phenylpentane.

A suspension of 235 mg (3.6 mmol) of zinc dust and 2.24 g (6.0 mmol) ofVCl₃.(tetrahydrofuran)₃ in 20 ml of dry dichloromethane was stirredunder N₂ atmosphere for 1 h at 25° C. Then 490 mg (3.3 mmol) of3,5-dimethylphenylacetaldehyde was added to it in one portion and asolution of 850 mg (3.0 mmol) of the resultant compound of Example 1A in20 ml of dichloromethane was added dropwise over a period of 40 min.After being stirred at ambient temperature under N₂ atmosphere for 6 h,the resulting mixture was added to 50 ml of 1M aqueous HCl and shakenvigorously for 1 min. The organic layer was washed with 1M aqueous HCl,separated, dried over MgSO₄, and concentrated in vacuo. Silica gelchromatography of the residue using 20% ethyl acetate in hexane provided666.0 mg (51%) of the desired compound as a white solid. Mass spectrum:(M+H)⁺ =434.

B. (2S,3R,4S)-3-Acetoxy-4-bromo-2-(Cbz-amino)-5-(3,5-dimethylphenyl)-1-phenylpentane.

Using the procedure of Example 1C but replacing(2S,3R,4S,5S)-2,5-bis-(N-Cbz-amino)-3,4-dihydroxy-1,6-diphenylhexanewith the resultant compound of Example 154A provided, after silica gelchromatography using 25% ethyl acetate in hexane, 506.2 mg (62%) of thedesired compound as a colorless oil. Mass spectrum: (M+NH₄)⁺ =555.

C.(2S)-2-(Cbz-amino)-5-(3,5-dimethylphenyl)-1-phenylpent-3-ene-3,4-oxide.

A solution of 480 mg (0.89 mmol) of the resultant compound of Example154B and 72 mg (1.33 mmol) of sodium methoxide in 25 ml oftetrahydrofuran was stirred at ambient temperature for 2 h. The solutionwas diluted with dichloromethane, washed with water, dried over MgSO₄,and concentrated in vacuo. Silica gel chromatography of the residueusing 25% ethyl acetate in hexane provided 328.1 mg (89%) of the desiredcompound as a oil which solidified upon standing. Mass spectrum: (M+H)⁺=41-6.

D.(2S,3R,4S)-4-Azido-2-(Cbz-amino)-5-(3,5-dimethyl-phenyl)-3-hydroxy-1-phenylpentane.

Using the procedure of Example 6D but replacing the resultant compoundof Example 6C with the resultant compound of Example 154C provided 285.7mg (86%) of the desired compound as a white solid. Mass spectrum:(M+NH4)⁺ =476.

E.(2S,3R,4S)-2,4-Diamino-5-(3,5-dimethylphenyl)-3-hydroxy-1-phenylpentane.

Using the procedure of Example 6E but replacing the resultant compoundof Example 6D with the resultant compound of Example 154D provided 109.1mg (84%) of the desired compound as a white solid. Mass spectrum: (M+H)⁺=299.

F.(2S,4S)-2,4-Bis-(N-(N-((2-pyridinyl)methoxycarbonyl)valinyl)amino)-5-(3,5-dimethylphenyl)-3-hydroxy-1-phenylpentane.

Using the procedure of Example 6G but replacing the resultant compoundof Example 6F with the resultant compound of Example 154E and replacingN-Cbz-valine p-nitrophenyl ester with the resultant compound of Example2D provided 142.7 mg (69%) of the desired compound as a white solid. ¹ HNMR (CDCl₃) δ0.67 (d, 3H), 0.79 (d, 3H), 0.88 (d, 3H), 0.92 (d, 3H),2.04 (m, 1H), 2.22 (s, 6H), 2.31 (m, 1H), 2.83 (m, 1H), 3.07 (m, 3H),3.62 (m, 2H), 3.78 (br t, 1H), 3.96 (m, 1H), 4.10 (dd, 1H), 5.02-5.17(m, 6H), 5.76 (br d, 1H), 6.21 (br d, 1H), 6.77 (br d, 3H), 7.09-7.31(m, 9H), 7.66 (m, 2H), 8.52 (dd, 2H). Mass spectrum: (M+H)⁺ =767.

EXAMPLE 155

(2S,3S,5S)-2,5-Bis-(N-(N-((2-pyridinyl)methoxycarbonyl)valinyl)amino)-1,6-diphenyl-3-(trichloroacetoxy)hexane.

Using the procedure of Example 35 but replacing trifluoroaceticanhydride with trichloroacetic anhydride provided, after silica gelchromatography using 5% methanol in dichloromethane, 102.8 mg (86%). ofthe desired compound as a white solid. ¹ H NMR (CDCl₃) δ0.71 (d, 3H),0.74 (d, 3H), 0.82 (d, 3H), 0.85 (d, 3H), 1.69 (m, 1H), 1.93 (m, 1H),2.07 (m, 2H), 2 . 72 (m, 2H), 2.86 (m, 2H), 3.81 (br t, 1H), 3.89 (br t,1H), 4 . 53 (br, 1H), 4.93 (m, 2H), 5.16-5.25 (m, 6H), 5.92 (br, 1H),6.03 (br d, 1H), 7.12-7.24 (m, 12H), 7.36 (br t, 2H), 7.73 (br 2H), 8.61(br d, 2H). Mass spectrum: (M+H)⁺ =97.

EXAMPLE 156

(2S,3S,5S)-2,5-Bis-(N-(N-((2-pyridinyl)methoxycarbonyl)valinyl)amino)-1,6-diphenyl-3-(propanoxy)hexane

Using the procedure of Example 35 but replacing trifluoroaceticanhydride with propanoic anhydride provided 106.1 mg (99%) of thedesired compound as a colorless crystal. ¹ H NMR (CDCl₃) δ0.77 (d, 6H),0.85 (two d, 6H), 1.15 (t, 3H), 1.56 (m, 1H), 1.67 (m, 1H), 2.03 (m,2H), 2.32 (q, 2H), 2.73 (m, 4H), 3.85 (m, 2H), 4.28 (m, 1H), 4.56 (m,1H), 4.89 (m, 1H), 5.23 (s, 4H), 5.35 (br, 2H), 6.00 (br, 2H), 7.06-7.36(m, 14H), 7.72 (br t, 2H), 8.59 (br s, 2H). Mass spectrum: (M+H)⁺ 809.

EXAMPLE 157

(2S,3S,5S)-2,5-Bis-(N-(N-((2-pyridinyl)methoxycarbonyl)valinyl)amino)-1,6-diphenyl-3-(methoxyacetoxy)hexane.

A suspension of 100 mg (0.13 mmol) of the resultant compound of Example2E and 24.3 mg (0.20 mmol) of 4-dimethylaminopyridine in 10 ml ofdichloromethane was treated with 0.017 ml (0.20 mmol) of methoxyacetylchloride. The resulting mixture was stirred at ambient temperature for 1h and then quenched with pH 6 buffer. The aqueous layer was extractedwith dichloromethane. The combined organic layers was dried over MgSO₄,and concentrated in vacuo to provide 107.0 mg (98%) of the desiredcompound as a white solid. ¹ H NMR (CDCl₃) δ0.74 (d, 3H), 0.77 (d, 3H),0.83 (d, 3H), 0.86 (d, 3H), 1.66 (m, 2H), 2.04 (m, 2H), 2.73 (m, 4H),3.45 (s, 3H), 3.86 (m, 2H), 4.01 (m, 2H), 4.32 (m, 1H), 4.63 (m, 1H),4.98 (m, 1H), 5.22 (br s, 5H), 5.30 (br d, 1H), 5.92 (br d, 1H), 6.11(br d, 1H), 7.07 (br d, 2H), 7.15-7.24 (m, 10H), 7.36 (br t, 2H), 7.71(tt, 2H), 8.59 (br t, 2H). Mass spectrum: (M+H)⁺ =825.

EXAMPLE 158

(2S,3S,5S)-2,5-Bis-(N-(N-((2-pyridinyl)methoxycarbonyl)valinyl)amino)-1,6-diphenyl-3-(formoxy)hexane.

Using the procedure of Example 35 but replacing trifluoroaceticanhydride with acetic formic anhydride provided 106.3 mg (100%) of thedesired compound as a white solid, m.p. 206-207 ° C. ¹ H NMR (CDCl₃)δ0.73 (two d, 6H), 0.84 (two d, 6H), 1.68 (m, 2H), 2.06 (m, 2H),2.65-2.79 (m, 4H), 3.85 (m, 2H), 4.36 (br, 1H), 4.68 (br q, 1H), 5.00(br t, 1H), 5.14-5.28 (m, 6H), 5.87 (br, 1H), 6.04 (br d, 1H), 7.07 (brd, 2H), 7.13-7.23 (m, 10H), 7.34 (br d, 2H), 7.69 (td, 2H), 8.04 (br,1H), 8.58 (br t, 2H). Mass spectrum: (M+H)⁺ =781.

Anal. Calcd for C₄₃ H₅₂ N₆ O₈.0.5H₂ O: C, 65.38; H, 6.76; N, 10.64;Found: C, 65.69; H, 6.75; N, 10.60.

EXAMPLE 159

(2S,3S,5S)-2,5-Bis-(N-(N-((N-methyl-N-methyl)amino)carbonyl)valinyl)amino)-1,6-diphenyl-3-dimethylamino)acetoxy)hexane

A.(2S,3S,5S)-2,5-Bis-(N-(N-((N-methyl-N-((2-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-1,6-diphenyl-3-(bromoacetoxy)hexane.

A suspension of 100 mg (0.13 mmol) of the resultant compound of Example3G and 23.5 mg (0.19 mmol) of 4-dimethylaminopyridine in 2 ml ofdichloromethane was treated with 0.022 ml (0.26 mmol) of bromoacetylbromide. The resulting mixture was stirred at ambient temperature for 5h and then quenched with pH 6 buffer. The organic layer was diluted withdichloromethane, separated, dried over Na₂ SO₄, and concentrated invacuo to provide, after silica gel chromatography using 10%-methanol indichloro-methane, 97.8 mg (85%) of the desired compound as a whitesolid. Mass spectrum: (M+H)⁺ =899.

B.(2S,3S,5S)-2,5-Bis-(N-(N-((N-methyl-N-((2-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-1,6-diphenyl-3-((N,N-dimethylamino)acetoxy)hexane.

A solution of 115.5 mg (0.13 mmol) of the resultant compound of Example159A in 5 ml of dichloromethane was treated with 0.020 ml (0.26 mmol) ofdimethylamine (1.3M in diethyl ether). After being stirred at ambienttemperature for 0.5 h, the solution was diluted with dichloromethane,washed with water, dried over Na₂ SO₄, and concentrated in vacuo. Silicagel chromatography of the residue using 5% methanol in dichloromethaneprovided 81.7 mg (73%) of the desired compound as a white solid, m.p.109-111° C. ¹ H NMR (CDl₃) δ0.79-0.88 (four d, 12H), 1.12 (m, 1H), 1.19(m, 1H), 2.13 (m, 2H), 2.37 (s, 6H), 2.61-2.84 (m, 4H), 2.98 (s, 6H),3.13 (br s, 2H), 4.04 (m, 2H), 4.30 (m, 1H), 4.43-4.58 (m, 5H), 5.02 (brt, 1H), 6.01 (br, 1H), 6.12 (br, 1H), 6.20 (br, 2H), 6.52 (br d, 1H),7.06-7.27 (m, 14H), 7.69 (m, 2H), 8.53 (m, 2H). Mass spectrum: (M+H)⁺=864.

Anal. Calcd for C₄₈ H₆₅ N₉ O₆ : C, 66.72; H, 7.58; N, 14.59; Found: C,66.35; H, 7.55; N, 14.69.

EXAMPLE 160

(2S,3S,5S)-2,5-Bis-N-(N-((N-methyl-N-2-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-1,6-diphenyl-3-(1-2-propoxy)ethoxy)hexane.

A solution of 80 mg (0.10 mmol) of the resultant compound of Example 3Gand 40 mg (0.16 mmol) of pyridium p-toluenesulfonate in 4 ml ofacetonitrile was treated with 4 ml of isopropyl vinyl ether. Theresulting mixture was stirred at ambient temperature under N₂ for 20 hand then quenched with pH 6 buffer. The aqueous layer was extracted withdichloromethane. The combined organic layers were dried over Na₂ SO₄ andconcentrated in vacuo. Silica gel chromatography of the residue using10% methanol in dichloromethane provided 86.1 mg (97%) of the desiredcompound as a white solid. ¹ H NMR (CDCl₃)6 0.73 (d, 3H), 0.77 (d, 3H),0.86 (two d, 6H), 1.08 (m, 6H), 1.24 (dd, 3H), 1.61-1.75 (m, 3H), 2.12(m, 1H), 2.21 (m, 1H), 2.64-2.92 (m, 4H), 2.96 (two d, 6H), 3.53-3.75(m, 2H), 4.00-4.14 (m, 2H), 4.33-4.64 (m, 6H), 5.94-6.47 (m, 4H),7.10-7.24 (m, 14H), 7.22 (td, 2H), 8.54 (m, 2H). Mass spectrum: (M+H)⁺=864.

Anal. Calcd for C₄₉ H₆₈ N₈ O₆ : C, 68.03; H, 7.92; N, 12.95; Found: C,67.67; H, 7.90; N, 12.95.

EXAMPLE 161

(2S,3S,5S)-2,5-Bis-(N-(N-((N-methyl-N-((2-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-1,6-diphenyl-3-(((N-(2-hydroxyethyl)-N-methyl)amino)acetoxy)hexane.

A solution of 100 mg (0.11 mmol) of the resultant compound of Example159A in 5 ml of dichloromethane was treated with 0.018 ml (0.22 mmol) of2-(methylamino)-ethanol. After being stirred at ambient temperature for1 h, the solution was diluted with dichloromethane, washed with water,dried over Na₂ SO₄, and concentrated in vacuo. Silica gel chromatographyof the residue using 10% methanol in dichloromethane provided 27.9 mg(28%) of the desired compound as a white solid. ¹ H NMR (CDCl₃) δ0.79(d, 6H), 0.84 (t, 6H), 1.73 (br, 2H), 2.08 (m, 1H), 2.17 (m, 1H), 2.48(s, 3H), 2.64-2.84 (m, 6H), 2.96 (s, 3H), 3.00 (s, 3H), 3.43 (br, 1H),3.72 (br, 2H), 4.04 (m, 2H), 4.38 (m, 1H), 4.42-4.57 (m, 6H), 5.07 (td,1H), 6.09 (br, 2H), 6.97 (br d, 2H), 7.08-7.2 6 (m, 14H), 7.69 (td, 2H),8.52 (m, 2H). Mass spectrum: (M+H)⁺ =894.

Anal. Calcd for C₄₉ H₆₇ N₉ O₇.CH₃ OH: C, 64.84; H, 7.73; N, 13.61;Found: C, 65.08; H, 7.52; N, 13.41.

EXAMPLE 162

(2S,3S,5S)-2,5-Bis-(N-(N-((N-methyl-N-((2-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-1,6-diphenyl-3-(((N-(2-acetoxyethyl)-N-methyl)amino)acetoxy)hexane.

A solution of 20.6 mg (0.023 mmol) of the resultant compound of Example161 and 5.6 mg (0.046 mmol) of 4-dimethylaminopyridine in 2 ml ofdichloromethane was treated with 3.3 μl (0.035 mmol) of aceticanhydride. The resulting mixture was stirred at ambient temperature for1.5 h and then quenched with pH 6 buffer. The organic layer was dilutedwith dichloromethane, separated, dried over Na₂ SO₄, and concentrated invacuo. Silica gel chromatography of the residue using 10% methanol indichloromethane provided 19.3 mg (92%) of the desired compound as awhite solid. ¹ H NMR (CDCl₃) δ0.80 (d, 6H), 0.86 (d, 6H), 1.60 (m, 1H),1.71 (m, 1H), 2.08 (s, 3H), 2.13 (m, 2H), 2.45 (s, 3H), 2.49-2.79 (m,4H), 2.84 (t, 2H), 2.97 (s, 6H), 3.29 (q, 2H), 4.04 (q, 2H), 4.17 (t,2H), 4.31 (m, 1H), 4.48 (br t, 4H), 4.56 (m, 1H), 5.01 (br t, 1H), 6.01(br, 1H), 6.12 (br, 1H), 6.21 (br d, 1H), 6.48 (br d, 1H), 7.07-7.25 (m,14H), 7.68 (m, 2H), 8.53 (br t, 2H). Mass spectrum: (M+H)⁺ =936.

Anal. Calcd for C₅₁ H₆₉ N₉ O₈ : C, 65.43; H, 7.43; N, 13.47; Found: C,65.18; H, 7.10; N, 13.42.

EXAMPLE 163

(2S,3S,5S)-2,5-Bis-(N-(N-((N-methyl-N-((2-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-1,6-diphenyl-3-(acetoxymethoxy)hexane.

A. (2S,3S,5S)-2,5-Bis-(N-(benzylidene)amino)-1,6-diphenyl-3-hydroxyhexane.

A solution of 150 mg (0.53 mmol) of the resultant compound of Example 1Ein 6 ml of tetrahydrofuran was treated with 0.11 ml of benzaldehyde.After being stirred at ambient temperature under N₂ atmosphere for 3 h,concentrated in vacuo, and left on oil pump for 1 day to provide thecrude desired compound. Mass spectrum: (M+H)⁺ =461.

B.(2S,3S,5S)-2,5-Bis-(N-(benzylidene)amino)-1,6-diphenyl-3-(2-methyl-2-propenoxy)hexane.

A solution of the crude resultant compound of Example 163A in 6 ml oftetrahydrofuran was treated with 0.58 ml of 1M solution of sodiumbis(trimethylsilyl)amide in tetrahydrofuran at 0° C. under N₂atmosphere. The resulting mixture was stirred for 40 min and thentreated with 3-iodo-2-methylpropene. Stirring was continued at 0° C. for1 h and at ambient temperature for 5 h. Evaporating of the solventprovided the crude desired compound. ¹ H NMR (CDCl₃)6 1.71 (s, 3H), 2.07(m, 1H), 2.33 (m, 1H), 2.82-3.11 (m, 4H), 3.52 (m, 2H), 3.68 (m, 1H),3.94 (s, 2H), 4.80 (s, 1H), 4.92 (q, 1H), 7.02-7.37 (m, 16H), 7.54-7.58(m, 4H), 7.72 (s, 1H), 7.88 (s, 1H). Mass spectrum: (M+H)⁺ =515.

C. (2S,3S,5S)-2; 5-Diamino-1,6-diphenyl-3-(2-methyl-2-propenoxy)hexane.

A solution of the crude resultant compound of Example 163B in 6 ml oftetrahydrofuran was treated with 6 ml of 1M aqueous HCl and stirred atambient temperature for 1.5 h. The reaction mixture was extracted withthree 10 ml portions of hexane. The aqueous layer was neutralized withsodium bicarbonate and then extracted with five 10 ml portions ofdichloromethane. The combined organic layers was dried over Na₂ SO₄, andconcentrated in vacuo. Silica gel chromatography of the residue using 2%isopropylamine and 5% methanol in dichloromethane provided 114.0 mg(64%, 3 steps) of the desired compound as a oil. Mass spectrum: (M+H)⁺=339.

D.(2S,3S,5S)-2,5-Bis-(N-(N-((N-methyl-N-((2-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-1,6-diphenyl-3-(2-methyl)-2-propenoxy)hexane.

Using the procedure of Example 6G but replacing the resultant compoundof Example 6F with the resultant compound of Example 163C and replacingN-Cbz-valine p-nitrophenyl ester with the resultant compound of Example3F provided 228.4 mg (93%) of the desired compound as a white solid.Mass spectrum: (M+H)⁺ =833.

E.(2S,3S,5S)-2,5-Bis-(N-(N-((N-methyl-N-((2-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-1,6-diphenyl-3-(acetoxymethoxy)hexane.

A stream of ozone was passed through a solution of 150 mg (0.18 mmol) ofthe resultant compound of Example 163D in 9 mL of 5:1 CH₂ Cl₂ /MeOH at-78° C. until the faint blue color of ozone persisted. The mixture wasthen purged with N₂ for 10 min and then concentrated in vacuo. Theresidue and 11.1 mg (0.09 mmol) of 4-dimethylaminopyridine weredissolved in 6 ml of dichloromethane, 35.1 μl (0.27 mmol) oftriethylamine and 20.4 μl (0.22 mmol) of acetic anhydride were added.The resulting mixture was stirred at 40° C. for 2 h and then quenchedwith pH 6 buffer. The organic layer was diluted with dichloromethane,separated, dried over Na₂ SO₄, and concentrated in vacuo to provide,after silica gel chromatography using 10% 2-propanol in dichloromethane,90.7 mg (59%) of the desired compound as a white solid. ¹ H NMR (CDCl₃)δ0.72 (d, 3H), 0.78 (d, 3H), 0.84 (d, 6H), 1.54 (m, 1H), 1.73 (m, 1H),1.99 (s, 3H), 2.14 (m, 2H), 2.63-2.87 (m, 4H), 2.96 (s, 3H), 2.98 (s,3H), 3.66 (dd, 1H), 4.00-4.11 (m, 2H), 4.33 (m, 1H), 4.40-4.53 (m, 4H),4.62 (m, 1H), 5.18 (dd, 2H), 6.08 (br, 2H), 6.22 (br d, 1H), 6.28 (br d,1H), 7.08-7.23 (m, 14H), 7.71 (m, 2H), 8.54 (m, 2H). Mass spectrum:(M+H)⁺ =851.

Anal. Calcd for C₄₇ H₆₂ N₈ O₇.1-PrOH: C, 65.91; H, 7.74;

12.30; Found: C, 66.14; H, 7.64; N, 12.21.

EXAMPLE 164

(2S,3S,5)-2,5-Bis-(N-(3-(3-pyridinyl)propanoyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 6I but replacing the resultant compoundof Example 6H with the resultant compound of Example 1E and replacingtrans-3-(pyridinyl)-acrylic acid with 3-(3-pyridinyl)propanoic acidprovided 42.1 mg (47%) of the desired compound as a white solid. ¹ H NMR(DMSO-d6) δ 1.33 (m, 2H), 2.24 (t, 2H), 2.33 (t, 2H), 2.57-2.72 (m, 8H),3.59 (m, 1H), 4.07 (m, 2H), 4.76 (d, 1H),7.02 (d, 2H), 7.10-7.27 (m,10H), 7.52 (m, 3H), 7.58 (br d, 1H), 8.37 (m, 4H). Mass spectrum: (M+H)⁺=551.

EXAMPLE 165

(2S,3S,5S)-2,5-Bis-(N-(N-(3-pyridinyl)glycinyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 6I but replacing the resultant compoundof Example 6H with the resultant compound of Example 1E and replacingtrans-3-(pyridinyl)-acrylic acid with N-(3-pyridinyl)glycine provided29.1 mg (44 %) of the desired compound as a white solid. ¹ H NMR(DMSO-d6) δ1.39 (m, 2H), 2.55 (m, 2H), 2.67 (d, 2H), 3.43-3.58 (m, 5H),4.14 (m, 2H), 4 . 87 (d, 1H), 6.07 (br t, 1H), 6.16 (br t, 1H), 6.65 (m,2H), 7.01 (m, 4H), 7.11 -7.24 (m, 8H), 7.53 (br d, 1H), 7.65 (br d, 1H),7.78 (d, 2 H), 7.93 (t, 2H). Mass spectrum: (M+H)⁺ =553.

EXAMPLE 166

(2S,3S,5S)-2,5-Bis-(N-((3-pyrazinyl)methoxycarbonyl)-amino)-1,6-diphenyl-3-hydroxyhexane.

A. Phenyl ((2-pyrazinyl)methoxy)formate.

Using the procedure of Example 176 but replacing 2-(hydroxymethyl)pyridine with 2-(hydroxymethyl)pyrazine provided 188.9 mg (70%) of thedesired compound as a yellow oil.

B.(2S,3S,5S)-2,5-Bis-(N-((3-pyrazinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 176 but replacing the resultant compoundof Example 176A with the resultant compound of Example 166A provided21.2 mg (36%) of the desired compound as a white solid. ¹ H NMR (CDCl₃)δ1.70 (t, 2H), 2.78 (d, 2H), 2.88 (d, 2H), 3.12 (d, 1H), 3.72 (br, 1H),3.83 (m, 1H), 4.00 (m, 1H), 4.99 (br d, 1H), 5.22 (m, 5H), 7.09-7.27 (m,10H), 8.54 (m, 6H). Mass spectrum: (M+H)⁺ =557.

EXAMPLE 167

(2S,3S,5S)-2,5-Bis-(N-((5-pyrimidinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

A. p-Nitrophenyl ((5-pyrimidinyl)methoxy)formate.

Using the procedure of Example 175 but replacing 4-(hydroxymethyl)pyridine with 5-(hydroxymethyl)pyrimidine provided 433.4 mg (77.5%) ofthe desired compound as a white solid.

B.(2S,3S,5S)-2,5-Bis-(N-((3-pyrimidinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 175 but replacing the resultant compoundof Example 175A with the resultant compound of Example 167A provided45.8 mg (78%) of the desired compound as a white solid. ¹ H NMR (CDCl₃)δ1.66 (m, 2H), 2.76 (d, 2H), 2.85 (d, 2H), 2.88 (m, 1H), 3.67 (br, 1H),3.81 (m, 1H), 3.95 (m, 1H), 4.87-5.14 (m, 6H), 7.04-7.28 (m, 10H), 8.70(d, 4H), 9.19 (s, 2H). Mass spectrum: (M+H)⁺ =557.

EXAMPLE 168

(2S,3S,5S)-2,5-Bis-(N-((3.5-dimethyl-4-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

A. Phenyl ((3,5-dimethyl-4-isoxazolyl)methoxy)formate.

Using the procedure of Example 175 but replacing4-(hydroxymethyl)pyridine with 3,5-dimethyl-4-(hydroxymethyl)isoxazoleprovided 0.79 g (69%) of the desired compound as a pale yellow oil.

D.(2S,3S,5S)-2,5-Bis-(N-((3,5-dimethyl-4-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 175 but replacing the resultant compoundof Example 175A with the resultant compound of Example 168A provided57.1 m₉ (92%) of the desired compound as a white solid. ¹ H NMR(DMSO-d6) δ1.44 (br t, 2H), 2.11 (s, 6H), 2.28 (s, 3H), 2.30 (s, 3H),2.64 (m, 4H), 3.53 (m, 1H), 3.82 (m, 2H), 4.65 (d, 1H), 4.72 (m, 4H),6.80 (br d, 1H), 7.02 (br d, 1H), 7.06-7.21 (m, 10H). Mass spectrum:(M+H)⁺ =591.

EXAMPLE 169

(2S,3S,5S)-2-(N-(N-((N-methyl-N-((2-pyridinyl)methyl)amino)carbonyl)isoleucinyl)amino)-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

A mixture of 40 mg (0.095 mmol) of(2S,3S,5S)-2-amino-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanefrom Example 37B and 57.3 mg (0.14 mmol) of the resultant compound ofExample 16C in 1 ml of dry tetrahydrofuran was stirred at ambienttemperature for 16 h. The solvent was then removed in vacuo, and theresidue was purified by silica gel chromatography using 5% methanol indichloromethane provided 62.1 mg (96%) of the desired compound as awhite foamy solid. ¹ H NMR (CDCl₃) δ0.82 (t, 3H), 0.88 (d, 3H), 1.03 (m,1R), 1.23 (m, 1H), 1.65 (t, 2H), 1.97 (m, 1H), 2.72 (dd, 2H), 2.82 (dd,2H), 2.94 (s, 3H), 3.65 (br, 1H), 3.96 (br q, 1H), 4,09 (m, 2H), 4.44(s, 2H), 5.03 (dd, 2H), 5.32 (br d, 1H), 6. 49 (br d, 2H), 7.08-7.26 (m14H), 7.59 (br d, 1H), 7.71 (td, 1H), 8.49 (dt, 1H), 8.54 (dd, 2H). Massspectrum: (M+H)⁺ =681.

Anal. Calcd for C₃₉ H₄₈ N₆ O₅.0.5H₂ O: C, 67.90; H, 7.16; N, 12.18;Found: C, 67.71; H, 7.03; N, 12.13.

EXAMPLE 170

(2S,3S,5S)-2-(N-(N-((2-pyridinyl)methoxycarbonyl)isoleucinyl)amino)-5-(N-((3-pyridinyl)methoxycarbonyl)-amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 169 but replacing the resultant compoundof Example 16C with the resultant compound of Example 25C provided 37.4mg (77%) of the desired compound as a white solid. ¹ H NMR (CDCl₃) δ0.82(t, 3H), 0.84 (d, 3H), 0.97 (m, 1H), 1.25 (m, 1H), 1.64 (m, 2H), 1.86(m, 1H), 2.75 (br d, 2H), 2.84 (d, 2H), 3 .68 (m, 1H), 3.96 (br t, 2H),4.10 (m, 1H), 5.03 (dd, 2H), 5.13-5.32 (m, 4H), 6.28 (br d, 1H), 7.07(d, 2H), 7.17-7.27 (m, 11H), 7.32 (d, 1H), 7.58 (dr, 1H), 7.70 (td, 1H),8.56 (m, 3H). Mass spectrum: (M+H)⁺ =668.

Anal. Calcd for C₃₈ H₄₅ N₅ O₆.0.75H₂ O: C, 66.99; H, 6.88; N, 10.28;Found: C, 66.87 ; H, 6.66; N, 10.18.

EXAMPLE 171

(2S,3S,5S)-5-(N-(N-((N-methyl-N-((2-pyridinyl)methyl)amino)carbonyl)isoleucinyl)amino)-2-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane.

Using the procedure of Example 169 but replacing (2S,3S,5S)-2-amino-5-(N- ((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith (2S,3S,5S)-5-amino-2- (N((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane from Example 37B provided 62.1 mg (96%) ofthe desired compound as a white foamy solid. ¹ H NMR (CDCl₃) δ0.82 (t,3H), 0.86 (d, 3H), 1.02 (m, 1H), 1.18 (m, 1H), 1.62 (m, 2H), 2.03 (m,1H), 2.73 (br t, 2H), 2.84 (dd, 2H), 2.99 (s, 3H), 3.75 (br q, 1H), 4.06(dd, 1H), 4.19 (m, 2H), 4.43 (m, 2H), 5.04 (dd, 2H), 5.18 (br d, 2H),6.48 (br d, 1H), 6.57 (br, 1H), 7.07-7.27 (m, 14H), 7.60 (dt, 1H), 7.73(td, 1H), 8.47 (br d, 1H), 8.28 (br d, 2H). Mass spectrum: (M+H)⁺ =681.

Anal. Calcd for C₃₉ H₄₈ N₆ O₅.0.5H₂ O: C, 67 90; H, 7.16; N, 12.18;Found: C, 67,54; H, 7.01; N, 12,10.

EXAMPLE 172

(2S,3S,5S)-5-(N-(N-((2-pyridinyl)methoxycarbonyl)isoleucinyl)amino)-2-(N-((3-pyridinyl)methoxycarbonyl)-amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 171 but replacing the resultant compoundof Example 16C with the resultant compound of Example 25C provided 25.9mg (56%) of the desired compound as a white solid. ¹ H NMR (CDC13)5 0.80(t, 3H), 0.84 (d, 3H), 1.22 (m, 2H), 1.63 (m, 2H), 1.92 (m, 1H), 2.75(br t, 2H), 2.86 (br d, 2H), 3.67 (m, 1H), 3.80 (m, 1H), 3.94 (br t,1H), 4.16 (m, 1H), 5.04 (dd, 2H), 5.13-5.30 (m, 4H), 6.40 (br, 1H);7.09-7.34 (m 14H), 7.59 (br d, 1H), 7.62 (br d, 1H), 8.58 (m, 3H). Massspectrum: (M+H)⁺ =668.

Anal. Calcd for C₃₈ H₄₅ N₅ O₆.0.5H₂ O: C, 67 44; H, 6.85; N, 10.35;Found: C, 67.71; H, 6.72; N, 10.30.

EXAMPLE 173

(2S,3R,4R,5S)-2,4-Di-{N-(N-methyl-N-(2-pyridylmethyl)aminocarbonyl)-L-Valyl}amino-3,4-dihydroxy-1,6-di-(4-hydroxyphenyl)hexane

A.(2S,3R,4R,5S)-2,5-Di(toluenesulfonylamino)-1,6-di-(4-methoxymethyoxyphenyl)-3,4-O-isopropylidenehexane

To a solution of 1-iodo-4-methoxymethoxybenzene (2.112 mg, 8.0mmol)dissolved in anhydrous ether (25 mL) and cooled in a dryice/acetone bath was added 1.7M butyl lithium (5.2 mL, 8.8 mmol). After2 hours, the mixture was cannulated into a mixture of copper(I)bromidedimethylsulfide (820 mg, 4.0 mmol) in ether (10 mL) cooled to -30° C.After 30 minutes, 1,2-di(1-tosylaziridin-2-yl)-1-O,2-O-isopropylidineethane (492 mg, 1.0 mmol) in ether was added. The reaction mixture wasallowed to warm gradually to 0 ° C. and was stirred for 2 hours beforequenching with ammonium hydroxide/ammonium chloride. After 30 minutes,the mixture was filtered and the filtrate diluted with ethyl acetate,dried over magnesium sulfate and concentrated under reduced pressure.The residue obtained was chromatographed on silica gel eluting with 30%ethyl acetate in hexane to give the title compound (132 mg).

B.(2S,3R,4R,5S)-2,5-Diamino-3,4-O-isopropylidene-1,6-di(4-methoxymethoxyphenyl)hexane

The compound resulting from Example 173A (387 mg, 0.564 mmol) dissolvedin ether (10 mL) was added to liquid ammonia (125 mL) cooled in a dryice/acetone bath small pieces of sodium metal were added until the bluecolor remained; the color was maintained by adding small pieces ofsodium over the next 30 minutes. The reaction was quenched using solidammonium chloride, the cooling bath was removed and the ammonia allowedto evaporate. The residue was dissolved in methylene chloride, washedwith 1N sodium hydroxide, dried over magnesium sulfate, and concentratedunder reduced pressure to give crude title compound (211 mg).

C. (2S,3R,4R,5S)-2,5-Di-{N-[N-methyl-N-(2-pyridylmethyl)amino-carbonyl]-L-Valyl}amino-3,4-O-isopropylidene-1,6-di-4-hydroxyphenyl)hexane

The compound resulting from Example 173B (210 mg, 0.456 mmol) wastreated with N-[N-methyl-N-(2-pyridylmethyl)aminocarbonyl]-L-Valine4-nitrophenyl ester (610 mg, 1.5 mmol) in tetrahydrofuran (2 mL) anddimethylformamide (1 mL). The reaction mixture was stirred overnight atroom temperature and then concentrated under reduced pressure.Chromatography on silica gel eluting with 5% methanol in methylenechloride afforded the title compound (381 mg, 87%).

D.(2S,3R,4R,5S)-2,5-Di-{N-[N-methyl-N-(2-pyridyimethyl)amino-carbonyl]-L-Valyl}amino-3,4-dihydroxy-1,6-di(4-hydroxyphenyl)hexane

The compound resulting from Example 173C (233 mg, 0.244 mmol)wasdissolved in 90% trifluoroacetic acid in water (4 mL)and kept in afreezer overnight. The reaction mixture was diluted with methylenechloride and washed with sodium bicarbonate and sodium chloridesolutions. The separatory funnel was extracted withchloroform/methanol/isopropyl alcohol and the combined organic extractswere dried over magnesium sulfate and concentrated under reducedpressure. Chromatography on silica gel eluting with 10% methanol inmethylene chloride afforded the title product. ¹ H NMR (CD₃ OD, 300 MHz)δ0.77 (d, 6H), 0.80 (d, 6H), 1.90 (m, 2H), 2.74 (d, 4H), 3.94 (d, 2H),4.50 (m, 2H), 4.59 (d of d, 4H), 6.61 (m, 4H), 7.05 (m, 4H), 7.31 (m,4H), 7.83 (m, 2H), 8.50 (m, 2H). MS (FAB)m/e 827 (M+H)⁺.

EXAMPLE 174

(2S,3S,5S)-2,5-Di{N-[3-pyridylmethyl)oxy-carbonyl]amino}-3-hydroxy-1,6-diphenylhexane

To the compound resulting from Example 1E (2.205 g, 7.866 mmol)dissolved in anhydrous dimethylformamide (10 mL) was added((3-pyridinyl)methyl)-(4-nitrophenyl)carbonate (6.385 g, 0.0233 mmol).After 5.5 hours, the solvent was removed under reduced pressure and theresidue dissolved in methylene chloride, washed with sodium bicarbonateand brine, dried over magnesium sulfate and concentrated under reducedpressure. The residue obtained was chromatographed on silica gel elutingwith a gradient of methanol in methylene chloride (2%,5%,10%)to affordthe title compound (2.215 g, 52%). ¹ H NMR (DMSO-d6, 300 MHz) δ1.50 (m,2H), 2.50-2.75 (m, 4H), 3.55 (m, 1H), 3.87 (m, 2H), 4.98 (d, 4H), 6.95(d, 1H), 7.00-7.27 (m, 12H), 7.33 (m, 2H), 7.60 (m, 2H), 8.50 (m, 3H).Anal calcd for C₃₂ H₃₄ N₄ O₅.0.33 H₂ O: C, 68.64; H, 5.97; N, 9.89.Found: C, 68.57; H, 6.19; N, 10.00. MS (DCI/NH₃)m/e 555 (M+H)⁺.

EXAMPLE 175

(2S,3S,5S)-2,5-Di{N-[(4-pyridylmethyl)oxy-carbonyl]amino}-3-hydroxy-1,6-diphenylhexane

A. ((4-pyridinyl)methyl)-(4-nitrophenyl)carbonate

To a solution of 4-pyridylcarbinol (169 mg, 1.0 mmol) and4-methylmorpholine (NMM)(165 μL, 1.5 mmol) dissolved in methylenechloride (1.0 mL) and cooled in an ice bath was added(4-nitrophenyl)chloroformate (300 mg, 1.5 mmol). After 1.33 hours,additional methylene chloride (1 mL) was added. After 2.5 hours, thereaction mixture was treated with methylene chloride and water andfiltered. The filtrate was washed with water, saturated sodiumbicarbonate solution and brine, dried over magnesium sulfate andconcentrated under reduced pressure. The residue obtained waschromatographed on silica gel eluting with methylene chloride and 1%going to 2% methanol in methylene chloride to afford the title compound(83 mg).

B.(2S,3S,5S)-2,5-Di{N-[4-pyridylmethyl)oxy-carbonyl]amino}-3-hydroxy-1,6-diphenylhexane

The compound resulting from Example 175A (213 mg, 0.777 mmol) and thecompound resulting from Example 1E (70 mg, 0.246 mmol) were dissolved indimethylformamide (0.8 mL) and stirred at room temperature for 3 days.The solvent was removed under reduced pressure and the residue obtaineddissolved in chloroform, filtered, and the filtrate washed withsaturated sodium bicarbonate solution and brine, dried over magnesiumsulfate, and concentrated under reduced pressure. Chromatography onsilica gel eluting with 5% methanol in methylene chloride afforded thetitle compound. ¹ H NMR (DMSO-d₆, 300 MHz) δ1.50 (m, 2H), 2.50-2.75 (m,4H), 3.55 (m, 1H), 3.87 (m, 2H), 4.98 (d, 4H), 6.95 (d, 1H), 7.00-7.27(m, 12H), 7.33 (m, 2H), 8.50 (m, 3H). MS (DCI/NH₃) m/e 555 (M+H)⁺.

EXAMPLE 176

(2S,3S,5S)-2,5-Di{N-[2-pyridylmethyl)oxycarbonyl]amino}-3-hydroxy-1,6-diphenylhexane

A. (2-Pyridylmethyl)phenylcarbonate

To a solution of 2-pyridine carbinol (109 mg, 1.0 mmol) dissolved inmethylene chloride (3 mL)and NMM (165 μL, 1.5 mmol) and cooled in an icebath was added phenyl chloroformate (188 μL, 1.5 mmol) dissolved inmethylene chloride (1.0 mL) dropwise. The reaction mixture was stirredat 0° C. for 1 hour, diluted with methylene chloride, washed withsaturated sodium bicarbonate and brine, dried over magnesium sulfate,and concentrated under reduced pressure. The residue obtained waschromatographed on silica gel eluting with 40% ethyl acetate in hexaneto afford the title compound (176 mg).

B.(2S,3S,5S)-2,5-Di{N-[2-pyridylmethyl)oxy-carbonyl]amino}-3-hydroxy-1,6-diphenylhexane

The compound resulting from Example 1E (92.5 mg, 0.326 mmol) and thecompound resulting from Example 176A (310 mg, 1.35 mmol) were dissolvedin dimethylformamide (1 mL) and warmed at 60° C. for 6.5 hours, allowedto stand overnight at room temperature, and then heated at 80° C. for 4hours. The reaction mixture was concentrated under reduced pressure andthe residue obtained chromatographed on silica gel eluting with 5%methanol in methylene chloride to afford the title compound (104 mg). ¹H NMR (DMSO-d₆, 300 MHz) δ1.56 (m, 2H), 2.54-2.75 (m, 4H), 3.63 (m, 1H),3.90 (m, 2H), 4.73 (m, 1H), 4.80-5.06 (m, 4H), 7.04-7.30 (m, 17H), 7.72(m, 2H), 8.49 (m, 2H). MS (DCI/NH₃) m/e 555 (M+H)⁺.

EXAMPLE b 177

(2S,3S,5S)-2,5-Di{N-[Benzylaminocarbonyl]amino}-3-hydroxy-1,6-diphenylhexane

To a solution of the compound resulting from Example 1E (72.6 mg, 0.256mmol)dissolved in dimethylformamide (1 mL) was added benzyl isocyanate(95 μL, 0.768 mmol). The reaction mixture was stirred overnight at roomtemperature and then concentrated under reduced pressure. The residueobtained was chromatographed on silica gel eluting with a gradient ofmethanol .in methylene chloride (2%,5%) to afford the title compound. ¹H NMR (DMSO-d6, 300 MHz) δ1.40 (m, 2H), 2.54-2.80 (m, 4H), 3.62 (m 1H),3.90 (m, 1H), 4.01 (m, 1H), 4.98 (d, 1H), 5.71 (d, 1H), 5.83 (d, 1H),6.16 (m, 1H), 6.39 (m, 1H), 7.04 (m, 2H), 7.11-7.32 (m, 19H. MS (DCl/NH₃m/e 551 (M+H)⁺.

EXAMPLE 178

(2S,3S,5S)-2,5-Di[N-{[1-(3-pyridyl)ethyl]oxy-carbonyl}amino]-3-hydroxy-1,6-diphenylhexane

The compound resulting from Example 1E (70 mg, 0.246 mmol) and[1-(3-pyridyl)ethyl]-(4-nitrophenyl)carbonate (220 mg, 0.764 mmol) weredissolved in dimethylformamide (1.0 mL) and stirred at room temperaturefor 2.5 days. The reaction mixture was concentrated under reducedpressure and the residue obtained chromatographed on silica gel elutingwith a gradient of methanol in methylene chloride (2%, 5%, 10%, 20%)containing 0.5% ammonium hydroxide to afford the title compound (80.6mg). ¹ H NMR (DMSO-d₆, 300 MHz) δ1.30-1.56 (m, 8H), 2.36-2.78 (m, 4H),3.37-3.93 (m, 5H), 5.57 (m, 2H), 6.78-7.56 (m, 16H), 7.72 (m, 1H),8.40-8.60 (m, 4H). MS (DCI/NH₃) m/e 583 (M+H)⁺.

EXAMPLE 179

(2S,3S,5S)-2-[(tert-Butyloxycarbonyl)amino]-5-[N-{(3-pyridyl)methyloxycarbonyl}amino]-3-hydroxy-1,6-diphenyl

A.(2S,3S,5S)-2-Amino-5-[N-{(3-pyridyl)methyloxycarbonyl}amino]-3-hydroxy-1,6-diphenylhexane

The compound resulting from Example 1E (820 mg, 2.89 mmol) and(3-pyridylmethyl)phenyl carbonate (728 mg, 3.179 mmol) were dissolved indimethylformamide and warmed at 50° C. for 15.5 hours. The solvent wasremoved under reduced pressure and the residue obtained chromatographedon silica gel eluting with a gradient of methanol in methylene chloride(2%,5%,10%) to afford a mixture of compounds (919 mg). This material wasre-chromatographed on silica gel eluting with 2% methanol in methylenechloride containing 1% isopropylamine to afford the title compound (424mg, 35%). Also isolated was the regio-isomer in which substitutionoccurred at the 2-amino group instead of the 4-amino group.

B.(2S,3S,5S)-2-[(tert-Butyloxycarbonyl)amino]-5-[N-{(3-pyridyl)methyloxycarbonyl}amino]-3-hydroxy-1,6-diphenylhexane

To the product of Example 179A (92.5 mg, 0.215 mmol) dissolved inmethylene chloride was added di-t-butyldicarbonate (90 mg). After 2hours, additional di-t-butyldicarbonate (33 mg) was added. After anadditional hour, the reaction mixture was concentrated under reducedpressure. The residue obtained was chromatographed on silica gel elutingwith methanol in methylene chloride (2%,5%) to afford the title compound(194 mg, 79%). ¹ H NMR (DMSO-d₆, 300 MHz) δ 1.30 (s, 9H), 1.50 (m, 2H),2.53-2.74 (m, 4H), 3.52 (m, 1H), 3.72-3.97 (m, 3H), 4.58 (d, 1H),4.82-5.00 (m, 2H), 6.31 (bd, 1H), 7.10-7.27 (m, 15H), 7.34 (m, 1H), 7.58(m, 1H), 8.50 (m, 2H). MS (DCI/NH₃) m/e 520 (M+H)⁺.

EXAMPLE 180

(2S,3S,5S)-2-[(Benzyloxycarbonyl)amino]-5-[N-{(3-pyridyl)methyloxycarbonyl}amino]-3-hydroxy-1,6-diphenyl

To the product of Example 179A (76 mg, 0.1814 mmol) dissolved inmethylene chloride (2 mL) was added N-[benzyloxycarbonyl)oxy]succinimide(68 mg, 0.272 mmol). The reaction mixture was stirred overnight at roomtemperature and then concentrated under reduced pressure. The residueobtained was chromatographed on silica gel eluting with methanol inmethylene chloride (0%,2%,5%) to afford the title compound. ¹ H NMR(DMSO-d₆, 300 MHz) δ1.51 (m, 2H), 2.54-2.75 (m, 4H), 3.57 (m, 1H), 3.87(m, 2H), 4.68 (m, 1H), 4.72-4.90 (m, 1H), 4.96 (m, 4H), 6.90 (d, 1H),7.00-7.38 (m, 18H), 7.60 (m, 1H), 8.50 (m, 2H). MS (DCI/NH₃) m/e 554(M+H)⁺.

EXAMPLE 181

(2S,3S,5S)-5-[(tert-Butyloxycarbonyl)amino]-2-[N-{(3-pyridyl)methyloxycarbonyl}amino]-3-hydroxy-1,6-diphenylhexane

The compound resulting from isolation of the regio-isomer in Example179A (80 mg, 0.191 mmol) was reacted by the procedure described inExample 179B to give crude material. Chromatography on silica geleluting with methanol in methylene chloride (0%,2%,5%)afforded the titlecompound (87 mg, 88%). ¹ H NMR (DMSO-d₆, 300 MHz) δ1.30 (s, 9H), 1.46(m, 2H), 2.53-2.78 (m, 4H), 3.56 (m, 1H), 3.86 (m, 2H), 4.63 (bd, 1H),4.83-5.03 (m, 3H), 6.63 (bd, 1H), 6.90 (bd, 1H), 7.00-7.27 (m, 14H),7.34 (m, 2H), 7.59 (m, 1H), 8.49 (m, 2H). MS (DCI/NH₃) m/e 520 (M+H)⁺.

EXAMPLE 182

(2S,3S,5S)-5-[(Benzyloxycarbonyl)amino]-2-[N-{(3-pyridyl)methyloxycarbonyl}amino]-3-hydroxy-1,6-diphenylhexane.

The compound resulting from isolation of the regio-isomer in Example179A (80 mg, 0.191 mmol) was reacted withN-[benzyloxycarbonyl)oxy]succinimide (71 mg, 0.286 mmol) by theprocedure described in Example 180 to give, after column chromatographyon silica gel, the title compound (89.3 mg, 85%). ¹ H NMR (DMSO-d₆, 300MHz) δ1.50 (m, 2H), 2.53-2.74 (m, 6H), 3.57 (m, 1H), 3.87 (m, 2H), 4.68(m, 1H), 4.87 (m, 5H), 6.94 (bd, 1H), 7.00-7.37 (m, 18H), 7.60 (m, 1H),8.50 (m, 2H). MS (DCI/NH₃) m/e 554 (M+H)⁺.

EXAMPLE 183

(2S,3S,5S)-2,5-Di[N-{[(2-methylpyridin-5-yl)methyl]oxycarbonyl}amino]-3-hydroxy-1,6-diphenylhexane

2-Methylpyridine-5-carbinol (246 mg, 2.0 mmol) was converted to the4-nitrophenyl carbonate by the procedure described in Example 175A. Thecrude material was chromatographed on a silica gel column eluting with agradient of ethyl acetate in hexane (50%,90%) to give the carbonate. The300 MHz ¹ H NMR spectrum was found to be consistent with the proposedstructure.

The compound resulting from Example 1E (93 mg, 0.327 mmol) was reactedwith the above carbonate (282 mg, 0.981 mmol) in dimethylformamide (0.60mL) overnight at room temperature. The reaction mixture was concentratedunder reduced pressure and the residue obtained chromatographed onsilica gel eluting with a gradient of methanol in methylene chloride(2%,5%) to afford the title compound (103 mg, 54%). ¹ H NMR (DMSO-d₆,300 MHz) δ1.47 (m, 2H), 2.43 (bd, 6H), 2.53-2.74 (m, 4H), 3.52-3.60 (m,2H), 3.87 (m, 2H), 4.67 (bd, 1H), 4.68-4.83 (m, 1H), 4.91 (bd, 4H), 6.89(bd, 1H), 7.00-7.38 (m, 14H), 7.49 (d of d, 2H), 8.35 (m, 2H). MS(DCI/NH₃) m/e 583 (M+H)⁺.

EXAMPLE 184

(2S,3S,5S)-2,5-Di[N-{[2-(3-pyridyl)propan-2-yl]oxy-carbonyl}amino]-3-hydroxy-1,6-diphenylhexane

3-(2-Hydroxypropan-2-yl)pyridine (57 mg, 0.416 mmol) was converted tothe 4-nitrophenyl carbonate by the procedure described in Example 175A.The crude residue was chromatographed on silica gel eluting with 50%ethyl acetate in hexane to afford the carbonate. The 300 MHz ¹ H NMRspectrum was found to be consistent with the proposed structure.

The compound resulting from Example 1E (88 mg, 0.31 mmol) was reactedwith the above carbonate (281 mg, 0.93 mmol) in dimethylformamaide (0.60mL) overnight at room temperature. The reaction mixture was concentratedunder reduced pressure and the residue obtained chromatographed onsilica gel eluting with a gradient of methanol in methylene chloride(2%,5%,10%)to afford the title compound (109 mg). ¹ H NMR (DMSO-d₆, 300MHz) δ1.34-1.69 (m, 8H), 2.43-2.85 (m, 4H), 3.49 (m, 2H), 3.71 (m, 3H),4.57 (d, 1H), 6.72 (bd, 1H), 6.86-7.32 (m, 14H), 7.49 (m, 2H), 8.36 (m,2H), 8.51 (m, 2H). MS (DCI/NH₃) m/e 611 (M+H)⁺.

EXAMPLE 185

(2S,3R,4R,5S)-1,6-Di(propylamino)-2,5-di[N-(N-Cbz-Valyl)amino]-3,4-dihydroxyhexane

A.(2S,3R,4R,5S)-2,5-Di[N-(N-Cbz-Valyl)amino]-1,6-di(propylamino)-3,4-O-isopropylidenehexane

To the compound resulting from Example 186A (580 mg, 0.892 mmol) cooledin an ice bath was added n-propylamine (0.80 mL, 9.0 mmol). The reactionmixture was allowed to gradually warm to room temperature and thenconcentrated under reduced pressure. The crude product waschromatographed on silica gel eluting with a gradient of methanol inmethylene chloride (5%,10%) to afford the title compound (316 mg, 46%).

B.(2S,3R,4R,5S)-1.6-Di(propylamino)-2,5-di[N-(N-Cbz-Valyl)amino]-3,4-dihydroxyhexane

The compound resulting from Example 185A (100 mg) was treated with 90%trifluoroacetic acid in water (3 mL) for 2.5 days at room temperature.The reaction mixture was concentrated under reduced pressure and theresidue obtained treated with concentrated ammonium hydroxide andextracted with methylene chloride. The combined organic extracts werewashed with brine, dried over magnesium sulfate and concentrated underreduced pressure. The residue obtained was chromatographed on silica geleluting with a gradient of methanol in methylene chloride (5%,10%,20%)containing 0.5% ammonium hydroxide to afford the title compound (30 mg).¹ H NMR (CD₃ OD, 300 MHz) δ0.91 (t, 6H), 0.99 (d, 12H), 1.50 (m, 6H),2.06 (m, 3H), 2.50-2.84 (m, 8H), 2.97 (m, 3H), 3.85 (bd, 2H), 4.49 (m,2H), 7.34 (m, 10H). MS (DCI/NH3)m/e 729 (M+H)⁺.

EXAMPLE 186

(2S,3R,4R,5S)-1,6-Di(morpholin-1-yl)-2,5-di[N-(N-Cbz-Valyl)amino]-3,4-dihydroxyhexane

A. 1,2-Di[N-(N-Cbz-Valyl)aziridin-2-yl]-1,2-O-isopropylidene ethane

To 1,2-di(aziridin-2-yl)-1,2-isopropylidine ethane (2.5 g) and Z-Valine(3.51 g, 0.014 mmol) dissolved in tetrahydrofuran (30 mL) and cooled inan ice bath was added 1-ethyl-3-(3'-dimethylamino)-propylcarbodiimide(EDAC) (2. 684 g, 0.014 mmol) followed by triethylamine (1.95 mL). Thereaction mixture was allowed to warm to room temperature and stirredovernight. The mixture was diluted with ethyl acetate and washed withsaturated sodium bicarbonate solution until the washes were colorless.The organic phase was dried over magnesium sulfate and concentratedunder reduced pressure. The residue obtained was chromatographed onsilica gel eluting with 40% ethyl acetate in hexane to afford the titlecompound (1.324 g).

B.(2S,3R,4R,5S)-2,5-Di[N-(N-Cbz-Valyl)amino]-3,4-O-isopropylidene-1,6-di(morpholin-1-ylhexane

The compound resulting from Example 186A (750 mg, 1.154 mmol) wastreated with morpholine (2.0 mL) in an ice bath. The reaction mixturewas allowed to gradually warm to room temperature and stirred overnight.The excess amine was removed under reduced pressure and the residueobtained was chromatographed on silica gel eluting with 2% methanol inmethylene chloride to afford the title compound (677 mg).

C.(2S,3R,4R,5S)-1,6-Di(morpholin-1-yl)-2,5-di[N-(N-Cbz-Valyl)amino]-3,4-dihydroxyhexane

The compound resulting from Example 186B (160 mg) was created with 90%trifluoroacetic acid in water (3 mL) at room temperature for 2 days andthen concentrated under reduced pressure. Unreacted starting materialremained, so 90% trifluoroacetic acid in water (4 mL) was added and thereaction mixture was warmed at 35 ° C. overnight. The reaction mixturewas then concentrated under reduced pressure and the residue obtaineddissolved in methylene chloride, treated with ammonium chloride, washedwith saturated sodium bicarbonate solution and brine, dried overmagnesium sulfate, and concentrated under reduced pressure. The residueobtained was chromatographed on silica gel eluting with 10% methanol inmethylene chloride containing 0.5% ammonium hydroxide to afford thetitle compound (67 mg). ¹ H NMR (CD₃ OD, 300 MHz) δ0.97 (m, 12H), 2.13(m, 2H), 2.38 (m, 6H), 2.52 (m, 6H), 3.60 (m, 8H), 3.96 (bd, 2H), 4.41(m, 2H), 7.33 (m, 10H). MS (DCI/NH₃) m/e 785 (M+H)⁺.

EXAMPLE 187

(2S,3R,4R,5S)-1,6-Di(imidazol-1-yl)-2,5-di[N-(N-Cbz-Valyl)amino]-3,4-dihydroxyhexane

The compound resulting from Example 186A (330 mg, 0.508 mmol) wastreated with imidazole (2.761 g, 0.0406 mmol) in dimethyformamide (4 mL)at 100° C. for 3.5 hours. The solution was cooled to room temperatureand diluted with methylene chloride, washed with water, dried overmagnesium sulfate, and concentrated under reduced pressure. The residueobtained was chromatographed on silica gel eluting with a gradient ofmethanol in methylene chloride (5%,10%) containing 0.5% ammoniumhydroxide. The compound obtained was heated at 60° C. under vacuum toremove any residual imidazole to afford the title compound (258 mg,65%).

The above compound (250 mg, 0.318 mmol) was warmed in 2N hydrochloricacid (8 mL) at 80° C. for 2 hours. The reaction mixture was concentratedunder reduced pressure and chased with methanol and ethanol. The residueobtained was dissolved in chloroform, treated with ammonium hydroxide (2mL), and the organic phase separated. The organic phase was washed withbrine, dried over magnesium sulfate, and concentrated under reducedpressure to afford crude material. Chromatography on silica gel elutingwith a gradient of methanol in methylene chloride (5%,10%) containing0.5% ammonium hydroxide afforded the title compound (101.5 mg). ¹ H NMR(DMSO-d₆, 300 MHz) δ0.73 (m, 12H), 1.87 (m, 2H), 3.84 (m, 2H), 3.87-4.08(m, 4H), 4.56 (m, 2H), 5.06 (q, 4H), 5.11 (m, 2H), 6.80 (bs, 2H), 7.05(m, 2H), 7.14 (bd, 2H), 7.33 (m, 2H), 7.39 (m, 8H), 7.53 (m, 2H), 7.66(bd, 2H). MS (FAB) m/e 747 (M+H)⁺.

EXAMPLE 188

(2S,3R,4R,5S)-1,6-Diphenylamino-2,5-di[N-(N-Cbz-Valyl)amino]-3,4-dihydroxyhexane

The compound resulting from Example 186A (514 mg, 0.791 mmol) andaniline (3.725 g, 40 mmol)were heated in dimethylformamide (10 mL) in a100° C. oil bath for 22 hours. The solvent was removed under reducedpressure and the residue obtained chromatographed on silica gel elutingwith methylene chloride followed by a gradient of methanol in methylenechloride (1%,2%) to afford a residue which was re-chromatographed onsilica gel eluting with 30% ethyl acetate in methylene chloride toafford 1,6-diphenyl-2,5-di[N-(N-Cbz-Valyl)amino]-3-O,4-O-isopropylidenehexane (300 mg).

This compound (239 mg, 0.256 mmol) was treated with 2N hydrochloric acid(10 mL) in methanol (5 mL) at 50° C. for 2.5 hours. The solvent wasremoved under reduced pressure and the residue obtained dissolved inchloroform, treated with concentrated ammonium hydroxide, washed withwater and brine, dried over magnesium sulfate, and concentrated underreduced pressure. The residue obtained was chromatographed on silica geleluting with a gradient of methanol in methylene chloride. (2%,5%) toafford the title compound (142 mg). ¹ H NMR (DMSO-d₆, 300 MHz) δ0.84 (dof d, 12H), 1.98 (m, 2H), 3.01 (m, 2H), 3.14 (m, 2H), 3.47 (bs, 2H),3.91 (m, 2H), 4.27 (m, 2H), 4.89 (bs, ¹ H), 5.06 (d of d, 6H), 6.53 (m,7H), 7.04 (m, 4H), 7.36 (m, 12H), 7.66 (bd, 2H). MS (DCI/NH₃) m/e 797(M+H)⁺.

EXAMPLE 189

2(S),5(S)-diamino-1,6-diphenyl-3,3-difluoro-4(R)-hydroxyhexane.

A. Ethyl4(S)-((t-butyloxycarbonyl)amino-5-phenyl-2,2-difluoro-3(R)-hydroxypentanoate.

To a solution of 9.6 gm of Boc-L phenylalaninal in 100 ml of THF wasadded 10 gm of zinc dust. To this sonicated mixture was added over 1.5hours a total of 10 ml of ethyl bromidifluoroacetate. The reactionmixture was filtered through celite and concentrated. The residual oilwas dissolved in ethyl acetate and washed with 10% KHSO₄. The combinedorganic layer was washed with brine, dried and concentrated. The mixtureof 3(R) and 3(S) isomers were purified by HPLC using 10% EtOAc in hexaneas eluting solvent to provide 4.1 gm of pure 3(R) isomer. m.p. 137°-139°C.

B. 2-Oxazolidinone derivative of Ethyl4(S)-Amino-5-phenyl-(2,2-difluoro-3(R)-hydroxypentanoate.

To 26.7 mmole of the resultant product from 189A was added 30 ml of 4NHCl in dioxane. The solution was stirred at RT for 1 hour. The solventwas removed in vacuo and the hydrochloride was dried on high vacuum for18 hours. To this hydrochloride was added at 0° C. 300 ml ofdichloromethane and 4.1 ml of triethylamine, then 2.84 gm oftriphosgene. After 1 hour at 0° C., 8.2 ml of TEA and 0.41 gm oftriphosgene were added. After 1.5 hours at 0° C. and 0.5 hours at RT,the reaction mixture was washed with 1N HCl and extracted withdochloromethane. The combined organic layer was washed with brine anddried and concentrated. Silica gel column chromotography (5% EtOAc inCH₂ CL₂)provided 6.1 gm (76%) of the desired product.

C. 2-Oxazolidinone derivative of N,O-dimethylhydroxy-amide of4(S)-amino-5-phenyl-2,2-difluoro-3(R)-hydroxypententanoic

To a solution of 10.86 gm of the resultant compound from Example 189B in200 ml of dioxane and 100 ml of water was added 2.28 gm of lithiumhydroxide. The solution was stirred at RT for 0.5 hr and the solvent wasremoved in vacuo. The residual oil was dissolved in EtOAc and acidifiedwith 1N HCl; the aqueous phase was extracted with EtOAc. The EtOAcsolution was washed with brine, dried and concentrated to give 9.54 gmof carboxylic acid. To 5.93 gm of this acid in 1t0 ml of dry DMF wasadded 6.42 gm of EDAC, 2.72 gm of N,O-dimethyl hydroxylaminehydrochloride and 9.1 ml of TEA. The reaction mixture was stirred at RTovernight, filtered and concentrated in vacuo. The residue was dissolvedin EtOAc and acidified with 1N HCl. The aqueous phase was extracted withEtOAc; the combined organic layer was dried concentrated. The crudeproduct was purified by silica gel column chromotography to give 6.34 gmof desired product (94%).

D. 4(S)-Benzyl-5(R)-(3'(3',3'-difluoro-2'-oxo-1'-phenyl))propyl-2-oxazolidinone.

To a solution of 6.45 gm of the resultant compound from Example 189C in200 ml of dry THF at -78° C. was added 30.8 ml of a 2M solution ofbenzylmagnesium chloride. The reaction mixture was stirred for 1 hour at-78° C., 1 hour at -20° C. finally 1 hour at 0° C. The reaction wasquenched with satd. NH₄ Cl solution, concentrated and extracted withEtOAc. The crude product was purified by silica gel columnchromotography (5% EtOAc in CH₂ Cl₂) to give 6.59 gm of desired product(93%).

F. Oxime derivative of4(S)-Benzyl-5(R)-(3'(3',3'-difluoro-2'-oxo-1'-phenyl))-propyl-2-oxazolidinone.

To a solution of 0.6 gm of the resultant product from Example 189D in 15ml of ethanol was added 0.24 gm of hydroxylamine hydrochloride and 0.42ml of pyridine. The solution was refluxed for 1 hour, cooled to RT andconcentrated. The residue was taken up in EtOAc and washed with 1N HCland then satd. brine, dried and concentrated. Purification by silica gelcolumn chromatography (20% EtOAc in CH₂ Cl₂) provided 0.64 gm of desiredproduct (98%).

F.4(S)-Benzyl-5(R)-(3'(3',3'-difluoro-2'(S)-amino-1'-phenyl))-propyl-2-ozaxolidinone.

To a solution of 2 gm of oxime from Example 189E in 100 ml each ofEtOAc/EtOH was added 25 gm of Raney Nickel Catalyst. The mixture wasshaken in a bomb at 1500 psi of hydrogen for 2 days. Filtration andconcentration in vacuo provided a mixture of 2'(S)- and 2'(R)-aminewhich was separated by silica gel column chromotography (1:1 EtOAc/CH₂Cl₂) to provide 0.59 gm of 2'(S)-amine and 0.83 gm of 2'(R)-amine. TheX-ray crystallography of a single crystal of the 2'(R)-amine establishthe absolute stereochemistry.

G. 2(S), 5(S)-diamino-1,6-diphenyl-3,3-difluoro-4(R)-hydroxyhexane.

To a solution of 1.03 gm of the resultant compound from Example 189F in60 ml of dioxane and 60 ml of water was added 2.5 gm of bariumhydroxide. The reaction mixture was heated to reflux for 4 hours, cooledto RT, filtered and concentrated. The aqueous solution was extractedwith ethyl acetate (3×100 ml). dried with anhydrous Na₂ SO₄ andconcentrated to give 930 mg of the desired product. ¹ H NMR (CDCl₃):δ1.3-1.5 (brm, 4H), 2.50 (m, 1H), 2.70 (m, 1H), 2.90 (m, 1H), 3.15 (m,1H), 3.45 (m, 1H), 3.72 (m, 1H). Mass spectrum: (M+H)⁺ =321.

EXAMPLE 190

2(S),5(S)-Bis-(Cbz-Valinyl)amino-1,6-diphenyl-3,3-difluoro-4-oxo-hexane.

Using the resultant product from Example 189G, and coupling toCbz-Valine using the carbodiimide procedure, followed by oxidation usingsodium dichromate in acetic acid (Synthesis, 466, (1989))provided thedesired product. ¹ H NMR (DMSO-d₆): δ0.62 (d, 3H), 0.65 (d, 3H), 0.70(d, 3H), 0.72 (d, 3H), 0.78 (d, 3H), 1.80 (m, 2H), 3.80 (m, 2H), 5.0 (s,4H), 7.10-7.40 (m, 20H). Mass spectrum: (M+H)=785.

EXAMPLE 191

2(S),5(S)-Bis-(2-pyridyl-methoxycarbonyl-valinyl)amino-1,6-diphenyl-3,3-difluoro-4-oxo-hexane.

Using the resultant compound from Example 189G and coupling to2-pyridyl-methoxycarbonyl-valine using the carbodiimide procedure,followed by oxidation with sodium dichromate in acetic acid provided thedesired product. ¹ H NMR (DMSO-d₆): δ0.70 (d, 3H), 0.78 (d, 3H), 0.80(d, 6H), 5.08 (s, 4H), 7.10-7.30 (m, 14H), 7.70 (m, 1H), 8.20 (m, 1H),8.50 (m, 1H), 8.60 (m, 1H). Mass spectrum: (M+H)⁺ =787.

EXAMPLE 192

2(S),5(S)-Bis-(N-(N-methyl-N-((2-pyridyl)methyl)amino)carbonyl)-valinyl-amino)-1,6-diphenyl-3,3.-difluoro-4(R)-hydroxybexane.

Using the resultant compound from Example 189G and coupling to (N-(N-methyl-N- ((2-pyridyl)methyl)amino)carbonylvaline using thecarbodiimide procedure provided the desired product in 68% yield. ¹ HNMR (DMSO-d₆): δ0.68 (d, 3H), 0.70 (m, 9H), 1.80 (m, 1H), 1.96 (m, 1H),2.88 (s, 3H), 2.90 (s, 3H), 5.90 (d, 1H), 6.02 (d, 1H), 6.20 (d, 1H),7.20-7.30 (m, 14H), 7.50 (d, 1H), 7.76 (m, 2H), 7.90 (d, 1H), 8.50 (m,2H). Mass spectrum: (M+H)⁺ =815.

EXAMPLE 193

2(S),5(S)-Bis-(N-(N-Methyl-N-((2-pyridyl)methyl)amino)carbonyl)-valinyl-amino)-1,6-diphenyl-3,3-difluoro-4-oxo-hexane.

Oxidation of the resultant product from Example 192 using sodiumdichromate in acetic acid provided the desired product in 60% yield. ¹ HNMR (DMSO-d₆): δ0.63 (d, 3H), 0.70 (d, 3H), 0 .75 (d, 3H), 0.77 (d, 3H),2.88 (s, 3H), 2.90 (s, 3H), 6.0 (d , 1H), 6.20 (d, 1H), 7.15-7.30 (m,14H), 7.70 (m, 2H), 8.20 (d, 1H), 8.50 (m, 2H), 8.60 (d, 1H). Massspectrum: (M+H )⁺ =813.

EXAMPLE 194

2(S),5(S)-Bis-(N-(3-(2-pyridyl)propenyl)-valinyl-amino)-1,6-diphenyl-3,3-difluoro-4(R)-hydroxy-hexane.

Using the resultant product from Example 189G and coupling to(N-(3-(2-pyridyl)propenoyl)-valine using the carbodiimide procedureprovided the desired product in 80% yield. ¹ H NMR (DMSO-d₆): δ0.70-0.80(m, 12H), 1.85 (m, 1H), 2.00 (m, 1H), 2.60-2.95 (m, 4H), 3.85 (m, 1H),4.30 (m, 1H), 4.60 (m, 1H), 4.80 (m, 1H), 7.10-7.60 (m, 18H), 7.80 (m,2H), 8.05-8.20 (m, 3H), 8.62 (m, 2H). Mass spectrum: (M+H)⁺ =781.

EXAMPLE 195

2(S),5(S)-Bis-(N-(3-(2-pyridyl)propanoyl)-valinyl-amino)-1,6-diphenyl-3,3-difluoro-4(R)-hydroxyhexane.

Hydrogenation of the resultant product from Example 194 using 10% Pd/cas catalyst and methanol as solvent provided the desired product inquantitative yield. ¹ H NMR (DMSO-d₆): δ0.62-0.70 (m, 12H), 1.75 (m,1H), 1.95 (m, 1H), 2.80-2.95 (m, 12H), 3.80 (m, 1H), 4.10 (m, 1H), 4.60(m, 1H), 4.80 (m, 1H), 6.02 (d, 1H), 7.18-7.22 (m, 14H), 7.46 (d, 1H),7.65 (m, 2H), 7.75 (d, 1H), 8.00 (d, 1H), 8.45 (m, 1H). Mass spectrum:(M+H )⁺ =785.

EXAMPLE 196

2(S),5(S)-Bis-(N-(3-(2-pyridyl)propanoyl)-valinyl-amino)-1,6-diphenyl-3,3-difluoro-4-oxo-hexane.

Oxidation of the resultant product from Example 195 using sodiumdichromate in acetic acid provided the desired product in 40% yield. ¹ HNMR (DMSO-d₆): δ0.70-0.80 (m, 12H), 7.15-7.30 (m, 12H), 7.60 (m, 2H),7.80 (d, 1H), 8.30 (d, 1H), 8.45 (m, 2H), 8.60 (d, 1H). Mass spectrum:(M+H)⁺ =783.

EXAMPLE 197

N-(2-(4-Pyridyl)ethanesulfonyl)valine.

To 1 gm of valine benzyl ester p-toluene-sulfonic acid salt in 40 ml ofCH₂ Cl₂ at 0° C. was added 1.12 gm of 4-pyridylsulfonyl chloride (U.S.Pat. No. 431504 (1982))and 1.9 ml of triethylamine. After 1 hour, thesolution was washed with water and extracted with CH₂ Cl₂ (2×100 ml),dried and concentrated. Silica gel column chromotography provided4-pyridyl-ethanesulfonyl-valine benzyl ester which was treated with 10%Pd/C in methanol under hydrogen atmosphere to provide the desiredproduct in 85% overall yield.

EXAMPLE 198

N-(2-(2-Pyridyl)ethanesulfonyl)valine.

Using the procedure of Example 197, but replacing4-pyridylethanesulfonyl chloride with 2-pyridylethanesulfonyl chlorideprovided the desired product in 82% overall yield.

EXAMPLE 199

2(S),5(S)-Bis-(N-(4-pyridylethanesulfonyl-valine)-amino)-1,6-diphenyl-3,3-difluoro-4(R)-hydroxyhexane.

Using the resultant product from Example 189G, and coupling to4-pyridylethanesulfonyl-valine using the carbodiimide procedure providedthe desired product in 70% yield. ¹ H NMR (DMSO-d₆): δ0.80 (m, 12H),1.90-2.10 (m, 2H), 2.30-3.00 (m, 12H), 3.60 (m, 1H), 3.70 (m, 1H), 3.98(m, 1H), 4.80 (m, 1H), 8.00 (m, 1H), 6.10 (d, 1H), 6.80-7.20 (m, 14H),7.40 (d, 1H), 7.90 (d, 1H), 8.20 (d, 1H), 8.45 (m, 4H). Mass spectrum:(M+H)⁺ =857.

EXAMPLE 200

2(S),5(S)-Bis-(N-(4-pyridylethanesulfonyl-valine)-amino)-1,6-diphenyl-3,3-difluoro-4-oxo-hexane.

Oxidation of the resultant product from Example 199 using the sodiumdichromate in acetic acid provided the desired product in 60% yield. ¹ HNMR (DMSO-d₆): δ0.90 (m, 12H), 2.00 (m, 1H), 2.20 (m, 1H), 6.80-7.30 (m,14H), 7.80 (d, 1H), 7.70 (d, 1H), 8.38-8.52 (m, 4H), 8.40 (d, 1H). Massspectrum: (M+H)=855.

EXAMPLE 201

2(S),5(S)-Bis-(N-(2-pyridylethanesulfonyl-valine)-amino)-1,6-diphenyl-3,3-difluoro-4(R)-hydroxyhexane.

Using the resultant product from Example 189G, and coupling to4-pyridylethanesulfonyl-valine provided the desired product in 75%yield. ¹ H NMR (DMSO-d₆): δ0.80 (m, 12H), 1.90-2.00 (m, 1H), 2.45-3.10(m, 12H), 3.60 (m, 1H), 3.70 (m, 1H), 3.80 (m, 1H), 4.70 (m, 1H), 4.90(m, 1H), 6.12 (d, 1H), 6.90-7.30 (m, 14H), 7.70 (m, 2H), 7.88 (d, 1H),8.40-8.50 (m, 2H). Mass spectrum: (M+H)⁺ =857.

EXAMPLE 202

2(S),5(S)-Bis(N-(2-pyridylethanesulfonyl-valine)-amino)-1,6-diphenyl-3,3-difluoro-4-oxo-hexane.

Oxidation of the resultant product from Example 201 using sodiumdichromate in acetic acid provided the desired product provided thedesired product in 53% yield. ¹ H NMR (DMSO-d₆): δ0.84 (m, 12H), 1.90(m, 2H), 2 .40-3.10 (m, 12H), 3.65 (m, 2H), 4.95-5.10 (m, 3H), 6.90-7.25(m, 15H), 7.55 (d, 1H), 7.75 (m, 2H), 8.46 (m, 2H), 8.40 (d, 1H). Massspectrum: (M+H)⁺ =855.

EXAMPLE 203

2(S),5(S)-Bis-(N-(4-pyridylethanesulfonyl-valinyl)-amino)-1,6-diphenyl-3(R),4(R)-dihydroxy-hexane.

Coupling of 4 -pyridylethanesulfonyl-valine to the resultant productfrom Example 4A provided the desired product in 51% yield. ¹ H NMR(DMSO-d₆): δ0.84 (m, 12H), 1.96 (m, 2H), 2.25 (m, 2H), 2.80-3.00 (m,12H), 3.70 (m, 2H), 4.80 (m, 2H), 6.80-7.20 (m, 14H), 7.80 (d, 2H), 8.45(m, 4). Mass spectrum: (M+H)⁺ =837.

EXAMPLE 204

2(S),5(S)-Bis-(N-(4-pyridylethanesulfonyl-valinyl)-amino)-1,6-diphenyl-3(S)-hydroxyhexane.

Coupling of 4-pyridylethanesulfonyl-valine to the resultant product fromExample 1E provided the desired product in 78% yield. ¹ H NMR -(DMSO-d₆): δ0.88 (m, 12H), 4.30 (m, 2H), 4.95 (d, 1H), 6.90-7.20 (m,14H), 7.25 (d, 1H), 7.32 (d, 1H), 7.30 (d, 1H), 7.90 (d, 1H), 8.46 (m,2H). Mass spectrum: (M+H)⁺ =821.

EXAMPLE 205

2(S),5(S)-Bis-(N-(2-pyridylethanesulfonyl-valinyll)-amino)-1,6-diphenyl-3(S)-hydroxy-hexane.

Coupling of 2-pyridylethanesulfonyl-valine to the resultant product fromExample 1E with the carbodiimide procedure provided the desired productin 88% yield. ¹ H NMR (DMSO-d₆): δ0.82 (m, 12H), 1.85 (m, 2H), 2.60-3.10 (m, 12H), 3.50 (m, 1H), 3.60 (m, 1H), 4.15-4.30 (m, 2H), 4.92(d, 1H), 6.90-7.25 (m, 14H), 7.70 (m, 1H), 7.75 (d, 1H), 7.80 (d, 1H),8.45 (m, 2H). Mass spectrum: (M+H)⁺ =821.

EXAMPLE 206

2(S),5(S)-Bis-(N-(2-pyridylethanesulfonyl-valinyl)-amino)-1,6-diphenyl-3(R),4(R)-dihydroxyhexane.

Coupling of 2-pyridylethanesulfonyl-valine to the resultant product fromExample 4A using the carbodiimide procedure provided the desired productin 70% yield. ¹ H NMR (DMSO-d₆): δ0.75 (d, 6H), 0.80 (d, 6H), 1.88 (m,2H), 2.55-3.10 (m, 12H), 3.60 (m, 2H), 4.65-4.80 (m, 4H), 6.90-7.35 (m,14H), 7.70 (m, 4H), 8.45 (m, 2H). Mass spectrum: (M+H)⁺ =837.

EXAMPLE 207

2(S),5(S)-Bis-(N-(4-pyridylethanesulfonyl-valine)-amino)-1,6-diphenyl-3(R)-4(S)-dihydroxyhexane.

Coupling of 4-pyridylethanesulfonyl-valine to the resultant product fromExample 13D using the carbodiimide procedure provided the desiredproduct in 65% yield. ¹ H NMR (DMSO-d₆): δ0.80 (m, 12H), 1.90 (m, 1H),2.10 (m, 1H), 2.30-3.00 (m, 12H), 3.60 (m, 1H), 3.70 (m, 1H), 4.30 (m,1H), 4.50 (m, 1H), 4.72 (d, 1H), 5.50 (d, 1H), 6.85-7.20 (m, 14H), 7.40(d, 1H), 7.90 (d, 1H), 8.20 (d, 1H), 8.45 (m, 4H). Mass spectrum: (M+H)⁺=837.

EXAMPLE 208

2(S),5(S)-Bis-(N-(4-pyridylethanesulfonyl-valinyl)-amino)-1,6-diphenyl-3(S),4(S)-dihydrozyhexane.

Coupling of 4-pyridylethanesulfonyl-valine to the resultant product fromExample 11C using the carbodiimide procedure provided the desiredproduct in 70% yield. ¹ H NMR (DMSO-d₆): δ0.83 (d, 6H), 0.90 (d, 6H),1.95 (m, 2H), 2.40-3.00 (m, 12H), 3.45 (m, 2H), 3.65 (m, 2H), 4.20 (m,2H), 4.90 (d, 2H), 6.90-7.20 (m, 14H), 7.40 (d, 2H), 8.20 (d, 2H), 8.40(m, 4H). Mass spectrum: (M+H)⁺ =837.

EXAMPLE 209

2(S),5(S)-Bis-(N-(2-pyridylethanesulfonyl-valinyl)-amino)-1,6-diphenyl-3(R),4(S)-dihydroxyhexane

Coupling of 2-pyridylethanesulfonyl-valine to the resultant product fromExample 13D using the carbodiimide procedure provided the desiredproduct in 60% yield. ¹ H NMR (DMSO-d₆): δ0.73 (d, 3H), 0.80 (d, 6H),0.85 (d, 3H), 1.85 (m, 2H), 2.55-3.05 (m, 12H), 3.88 (d, 3H), 3.70 (m,1H), 4.35 (m, 1H), 4.45 (m, 1H), 4.80 (d, 1H), 5.37 (d, 1H), 6.85-7.30(m, 14H), 7.70 (m, 2H), 7.80 (d, 1H), 8.10 (d, 1H), 8.45 (m, 1H), 8.50(m, 1H). (M+H)⁺ =837. Mass spectrum: (M+H)⁺ =837.

EXAMPLE 210

2(S),5(S)-Bis-(N-(2-pyridylethanesulfonyl-valinyl)-amino)-1,6-diphenyl-3(S),4(S)-dihydroxyhexane.

Coupling of 2-pyridylethanesulfonyl-valine to the resultant product from11C using the carbodiimide procedure provided the desired product in 82%yield. ¹ H NMR (DMSO-d₆): δ0.80 (m, 12H), 1.88 (m, 2H), 2.60-3.05 (m,12H), 3.50-3.60 (m, 4H), 4.20 (m, 2H), 5.0 (d, 2H), 6.90-7.30 (m, 16H),7.65 (m, 2H), 8.10 (d, 2H), 8.50 (m, 2H). Mass spectrum: (M+H)⁺ =837.

EXAMPLE 211

2(S),5(S)-Bis-(N-2-pyridylethanesulfonyl)-amino-1,6-diphenyl-3(S)-hydroxyhexane.

To a solution of 100 mg of the resultant product from Example 1E in 3 mlof dichloromethane was added 0.108 ml of triethylamine and 0.186 gm of2-pyridylethanesulfonyl chloride. After 0.5 hour at RT, the product waspurified by silica gel column chromotography to provide the desiredproduct in 35% yield. ¹ H NMR (CDCl₃): δ1.70-2.00 (m, 4H), 2.70-3.20 (m,10H), 3.65-3.95 (m, 3H), 5.00 (d, 1H), 5.18 (d, 1H), 7.00-7.28 (m, 14H),7.60 (m, 2H), 8.50 (m, 2 H). Mass spectrum: (M+H)⁺ =623.

EXAMPLE 212

2(S),5(S)-Bis-(N-2-pyridylethanesulfonyl)amino-1,6-diphenyl-3,3-difluoro-4(R)-hydroxyhexane.

To a solution of 150 mg of the resultant product from Example 189G in 5ml of dichloromethane was added 0.32 gm of triethylamine and 0.25 gm of2-pyridylethanesulfonyl chloride. After workup and purification bysilica gel column chromotography, 0.13 gm of desired product wasobtained. ¹ H NMR (CDCl₃): 8 1.90 (m, 4H), 2.50-2.70 (m, 4H), 2.90-3.10(m, 4H), 3.30 (m, 1H), 4.20-4.50 (m, 3H), 5.10 (d, 1H), 5.50 (d, 1H),7.00-7.30 (m, 14H), 7.60 (m, 2H), 8.50 (m, 2H). Mass spectrum: (M+H)⁺=659.

EXAMPLE 213

2(S),5(S)-Bis-(N-2-pyridylethanesulfonyl)amino-1,6-diphenyl-3,3-difluoro-4-oxo-hexane.

Oxidation of the resultant product from Example 212 using sodiumdichromate in acetic acid provided the desired product in 70% yield. ¹ HNMR (CDCl₃): δ2.60-3.40 (m, 12H), 4.40-4.60 (m, 2H), 5.0 (m, 2H),6.95-7.30 (m, 14H), 7.60 (m, 2H), 8.45-8.60 (m, 2H). Mass spectrum:(M+H)⁺ =657.

EXAMPLE 214

2(S),5(S)-Bis-(N-benzyloxycarbonyl)amino-1,6-diphenyl-3,3-difluoro-4(R)-hydroxyhexane.

To a solution of 30 mg of the resultant product from Example 189G in 1ml of DMF was added 0.1 gm of Cbz-NOS. The solution was stirred at RTfor 48 hours, concentrated in vacuo and purification by silica gelcolumn chromotography provided 29 mg of desired product. ¹ H NMR(CDCl₃): δ2.65 (m, 1H), 2.90 (m, 1H), 3.00 (m, 1H), 3.12 (m, 1H), 3.47(m, 1H), 3.88 (m, 1H), 4.38 (m, 1H), 4.68 (m, 1H), 4.90 (m, 1H), 5.00(s, 1H), 7.10-7.35 (m, 20H). Mass spectrum: (M+H)⁺ =589.

EXAMPLE 215

2(S),5(S)-Bis-N-benzyloxycarbonyl)amino-1,6-diphenyl-3,3-difluoro-4(R)-hydroxyhexane.

Oxidation of the resultant product from Example 214 using sodiumdichromate in acetic acid provided the desired compound in 80% yield. ¹H NMR (CDC13): 5 2.70 (m, 1H), 2.90 (m, 1H), 3.15 (m, 1H), 3.28 (m, 1H),4.70-5.15 (m, 8H), 7.10-7.40 (m, 20H). Mass spectrum: (M+H)⁺ =587.

EXAMPLE 216

2(S),5(S)-Bis-(N-3-pyridyl-methoxycarbonyl)amino-1,6-diphenyl-3,3-difluoro-4(R)-hydroxyhexane.

To a solution of 150 mg of the resultant product from Example 189G in 1ml of DMF was added 515 mg of the resultant product from Example 37A.After 48 hours at RT, solvent was removed in vacuo and purification bysilica gel column chromotography provided the desired compound in 81%yield. 1H NMR (CDCl₃): δ2.62 (m, 1H), 2.85-3.15 (m, 3H), 3.53 (m, 1H),3.90 (m, 1H), 4.40 (m, 1H), 4.70-5.20 (m, 6H), 7.10-7.60 (m, 14H),8.45-8.55 (m, 4H). Mass spectrum: (M+H)⁺ =591.

EXAMPLE 217

2(S),5(S)-Bis-(N-3-pyridyl-methoxycarbonyl)amino-1,6-diphenyl-3.3-difluoro-4-oxo-hexane.

Oxidation of the resultant compound from Example 216 using sodiumdichromate in acetic acid provided the desired product in 68% yield. ¹ HNMR (CDCl₃): δ2.70 (m, 1H), 2.90 (m, 1H), 3.15 (m, 1H), 3.30 (m, 1H),4.90-5.15 (m, 8H), 7.10-7.60 (m, 14H), 8.40-8.55 (m, 4H). Mass spectrum:(M+H)⁺ =588.

EXAMPLE 218

2 (S),5(S)-Bis-(N-(p-nitrophenoxycarbonyl)-amino)-1,6-diphenyl-3(S)-trimethylsiloxy-hexane.

To a solution of 200 mg of the resultant product from Example 1E in 5 mlof dichloromethane was added at 0° C. 0.112 ml of TEA and 0.098 ml oftrimethylsilyl chloride. After 30 minutes at 0° C., 0.215 ml of TEA and0.3 gm of p-nitrophenylchloroformate was added. After 1 hour at 0° C.,the solvent was removed in vacuo and the crude product purified bysilica gel column chromotography provided 0.3 gm of desired product. ¹ HNMR (CDCl₃): δ0.20 (s, 9H), 1.70 (m, 1H), 1.90 (m, 1H), 2.85 (m, 4H),3.90 (m, 1H), 4.00 (m, 1H), 4.20 (m, 1H), 4.90 (d, 1H), 5.30 (d, 1H),7.10-7.30 (m, 14H), 8.20 (m, 4H).

EXAMPLE 219

2(S),5(S)-Bis-(N-(3-pyridylmethylamino-carbonyl)-amino)-1,6-diphenyl-3(S)-hydroxyhexane.

To a solution of 87 mg of the resultant compound from Example 218 in 1ml of DMF was added 0.028 ml of 3-aminomethylpyridine. After 18 hours,the solvent was removed in vacuo and the residue was dissolved in 1 mlof methanol and 0.05 ml of chlorotrimethylsilane was added. After 0.5hour, the solvent was removed in vacuo, neutralized with sodiumbicarbonate solution and extraction with ethyl acetate (2×25 ml). Theorganic solution was dried and concentrated. Purification by silica gelcolumn chromotography provided 35 mg of desired product. ¹ H NMR (CD₃OD): δ1.60 (t, 2H), 2.60-2.80 (m, 4H), 3.70 (m, 1H), 4.00 (m, 1H), 4.10(m, 1H), 4.25-4.35 (m, 4H), 7.10-7.25 (m, 10H), 7.35 (m, 2H), 7.60 (m,2H), 8.40 (m, 4H). Mass spectrum: (M+H )⁺ =553.

EXAMPLE 220

2(S),5(S)-Bis-(N-(N-methyl-N-3-pyridylmethyl)carbonyl-amino)-1,6-diphenyl-3(S)-hydroxyhexane.

Using the procedure described in Example 219, but replacing3-aminomethylpyridine with N-methyl-3-aminomethylpyridine provided thedesired product in 50% yield. ¹ H NMR (CDCl₃): δ1.65 (m, 2H), 2.70 (s,3H), 2.74 (s, 3H), 2.80-3.00 (m, 4H), 3.70 (m, 1H), 3.82 (m, 1H), 4.02(m, 1H), 4.38-4.55 (m, 4H), 4.80 (d, 1H), 4.88 (d, 1H), 5.15 (d, 1H),7.10-7.30 (m, 12H), 7.48 (m, 2H), 8.45 (m, 2H), 8.50.(m, 2H). Massspectrum: (M+H)⁺ =581.

EXAMPLE 221

2 (S)-Amino-5(S)-(N-(N-methyl-N-(2-pyridyl)methyl)amino)carbonyl)-valinyl-amino)-1,6-diphenyl-3,3-difluoro-4(R)-hydroxyhexane.

To a solution of 250 mg of the resultant compound from Example 189 in 5ml of dry THF was added 440 mg of the resultant compound from Example3F. After 3 hours at RT, the solvent was evaporated in vacuo andpurification by silica gel column chromotography provided the desiredcompound in 70% yield. ¹ H NMR (CDCl₃): δ0.90 (d, 3H), 0.96 (d, 3H),2.20 (m, 1H), 2.60 (m, 1H), 2.85-3.05 (m, 2H), 3.00 (s, 3H), 3.20 (m,2H), 3.80-3.90 (m, 1H), 4.20 (m, 1H), 4.46-4.05 (m, 3H), 6.05 (m, 1H),6.76 (d, 1H), 7.10-7.30 (m, 12H), 7.70 (m, 1H), 8.52 (m, 1H). Massspectrum: (M+H)⁺ =568.

EXAMPLE 222

2(S)-(N-(3-pyridylmethoxycarbonyl)amino-5(S)-N-(N-methyl-N-((2-pyridyl)methyl)amino)carbonyl-valinyl-amino)-1,6-diphenyl-3,3-difluoro-4(R)-hydroxyhexane.

To a solution of 240 mg of the resultant compound from Example 221 in 2ml of DMF was added 230 mg of the resultant compound from Example D-37A.After 72 hours, the solvent was removed in vacuo. Purification by silicagel column chromotography provided the desired compound in 90% yield. ¹H NMR (CDCl₃): δ0.86 (d, 3H), 0.95 (d, 3H), 2.22 (m, 1H), 2.60 (m, 1H),2.95-3.20 (m, 3H), 2.96 (s, 3H), 3.90 (m, 1H), 4.05 (m, 1H), 4.40 (m,1H), 4.4 6 (s, 2H), 4.65 (m, 1H), 4.83 (d, 1H), 5.00 (d, 1H), 6.85 (d,1H), 7.10-7.30 (m, 14H), 7.40 (m, 1H), 7.70 (m, 1H), 8.45-8.55 (m, 3H).Mass spectrum: (M+H)⁺ =703.

EXAMPLE 223

2(S)-(N-(3-pyridylmethoxycarbonyl)amino-5(S)-(N-(N-methyl-N-((2-pyridyl)methyl)amino)carbonyl-valinyl-amino)-1,6-diphenyl-3,3-difluoro-4-oxo-hexane.

Oxidation of the resultant compound from Example 222 using sodiumdichromate in acetic acid provided the desired compound in 40% yield. ¹H NMR (CDCl₃): δ0.85 (d, 3H), 0.90 (d, 3H), 2.20 (m, 1H), 2.70-3.25 (m,4H), 2.95 (s, 3H), 4.10 (m, 1H), 4.40 (s, 2H), 4.80-5.00 (m, 2H),5.20-5.30 (m, 2H), 6.80 (d, 1H), 7.10-7.25 (m, 13H), 7.45 (m, 1H), 7.70(m, 1H) 8.45-8.50 (m, 3H). Mass spectrum: (M+H)⁺ =701.

EXAMPLE 224

2(S)-(Acetyl-amino-5(S)-(N-(N-methyl-N-(2-pyridyl)methyl)amino)carbonyl-valinyl-amino)-1,6-diphenyl-3,3-difluoro-4(R)-hydroxyhexane.

To a solution of 100 mg of the resultant compound from Example 221 in 2ml of dry THF was added at 0° C. 0.037 ml of TEA and 0.014 ml of acetylchloride. After 0.5 hour, solvent was evaporated in vacuo. Purificationby silica gel column chromotography provided 87 mg of desired compound.¹ H NMR (CDCl₃): δ0.90 (d, 3H), 0.95 (d, 3H), 1.70 (s, 3H), 2.20 (m,1H), 2.65 (m, 1H), 2.95-3.15 (m, 4H), 3.00 (s, 3H), 3.80 (m, 1H), 4.10(m, 1H), 4.40 (m, 1H), 4.50 (s, 2H), 4.70 (m, 1H), 5.40 (d, 1H), 5.48(d, 1H), 6.30 (m, 1H), 6.95 (d, 1H), 7.10-7.30 (m, 12H), 7.70 (m, 1H),8.50 (m, 1H). Mass spectrum: (M+H)⁺ =610.

EXAMPLE 225

2 (S)-(Acetyl-amino)-5(S)-(N-(N-methyl-N-(2-pyridyl)methyl)amino)carbonyl-valinyl-amino)-1,6-diphenyl-3,3-difluoro-4-oxo-hexane.

Oxidation of the resultant compound from Example 224 using sodiumdichromate in acetic acid provided the desired compound in 40% yield. ¹H NMR (CDCl₃): δ0.86 (d, 3H), 0.90 (d, 3H), 1.80 (s, 3H), 2.20 (m, 1H),2.70-3.30 (m, 4H), 2.98 (s, 3H), 4.10 (m, 1H), 4.40 (s, 2H), 5.05 (m,1H), 5.23 (m, 1H), 5.70 (d, 1H), 6.40 (m, 1H), 6.80 (d, 1H), 7.10-7.30(m, 12H), 7.70 (m, 1H), 8.46 (m, 1H). Mass spectrum: (M+H)⁺ =608.

EXAMPLE 226

2(S)-(N-Methoxycarbonyl-amino)-5(S)-(N-(N-methyl-N-(2-pyridyl)methyl)amino)carbonyl-valinyl-amino)-1,6-diphenyl-3,3-difluoro-4(R)-hydroxyhexane.

To a solution of 100 mg of the resultant compound from Example 221 in 2ml of dry THF was added 0.043 ml of TEA and 0.030 ml ofmethylchloroformate. After 24 hours at RT, the solvent was removed invacuo. Purification by silica gel column chromotography provided 52 mgof desired compound. ¹ H NMR (CDCl₃): δ0.88 (d, 3H), 0.95 (d, 3H), 2.20(m, 1H), 2.65-3.15 (m, 4H), 3.00 (s, 3H), 3.50 (s, 3H), 3.90 (m, 1H),4.05 (m, 1H), 4.40 (m, 1H), 4.48 (s, 2H), 4.55 (m, 1H), 4.70 (m, 1H),5.25 (d, 1H), 6.85 (m, 1H), 7.10-7.30 (m, 12H), 7.70 (m, 1H), 8.52 (m,1H). Mass spectrum: (M+H)⁺ =626.

Example 2272(S)-(N-Methoxycarbonyl-amino)-5(S)-(N-(N-methyl-N-(2-methyl)amino)carbonyl-valinyl-amino)-1,6-diphenyl-3,3-difluoro-4-oxo-hexane.

Oxidation of the resultant compound from Example 226 using sodiumdichromate in acetic acid provided the desired compound in 50% yield. ¹H NMR (CDCl₃): δ0.86 (d, 3H), 0.90 (d, 3H), 2.20 (m, 1H), 2.70-3.30 (m,4H), 3.00 (s, 3H), 3.50 (s, 3H), 4.10 (m, 1H), 4.42 (s, 2H), 4.70 (m,1H), 5.05 9m, 1H), 5.30 (m, 1H), 6.40 (m, 1H), 6.75 (d, 1H), 7.10-7.30(m, 12H), 7.70 (m, 1H), 8.50 (m, 1H). Mass spectrum: (M+H)⁺ =624.

Example 228 3(S),6(S)-Diamino-4,4-difluoro-5(R)-hydroxy-2-methyl-7-cyclohexylheptane

Using the procedure described in detail in Examples 189A to 189G, exceptreplacing Boc-L-phenylalaninal with Boc-L-cyclohexyl-alaninal andreplacing benzyl magnesium chloride with isopropyl magnesium chlorideprovided the desired compound. Mass spectrum: (M+H)⁺ =279.

Example 229 3(S),6(S)-Bis-(2-pyridyl-methoxycarbonyl-valinyl)amino-4,4-difluoro-5(R)-hydroxy-2-methyl-7-cyclohexylheptane

Using the resultant compound from Example 228 and coupling to2-pyridylmethoxyycarbonyl-valine using the carbodiimide procedureprovided the desired product in 75% yield. ¹ H NMR (CDCl₃): δ0.80-1.20(m, 22H), 1.60 (m, 6H), 2.15 (m, 3H), 3.70 (m, 1H), 4.00 (m, 1H),4.30-4.50 (m, 2H), 5.20 (m, 4H), 7.15 (m, 2H), 7.30 (m, 2H), 7.70 (m,2H), 8.55 (m, 2H). Mass spectrum: (M+H)⁺ =747.

Example 2303(S),6(S)-Bis-(2-pyridylmethoxycarbonyl-valinyl)amino-4,4-difluoro-5-oxo-2-methyl-7-cyclohexylheptane

Oxidation of the resultant compound from Example 229 using sodiumdichromate in acetic acid provided the desired compound in 60% yield. ¹H NMR (CDCl₃): δ0.90-1.80 (m, 21H), 2.00 (m, 1H), 2.15 (m, 1H), 3.95 (m,1H), 4.05 (m, 1H), 4.60 (m, 1H), 5.10 (m, 1H), 5.25 (m, 4H), 5.60 (m,1H), 6.30 (m, 1H), 7.20 (m, 2H), 7.40 (d, 2H), 7.70 (m, 2H), 8.60 (m,2H). Mass spectrum: (M+H)⁺ =745.

Example 231 3(S), 6(S)-Bis-(N-(N-methyl-N((2-pyridyl)methyl)amino)carbonyl-valinyl-amino)-4,4-difluoro-5(R)-hydroxy-2-methyl-7-cyclohexylheptane

Using the resultant compound from Example 228 and coupling to(N-(N-methyl-N-((2-pyridyl)methyl)amino)carbonyl-valine using thecarbodiimide procedure provided the desired compound in 68% yield. ¹ HNMR (CDCl₃): δ0.85 (d, 3H), 0.88 (d, 3H), 0.90 (d, 3H), 0.95 (d, 3H),1.00 (d, 3H), 1.03 (d, 3H), 1.10-1.60 (m, 13H), 2.20 (m, 2H), 2.35 (m,1H), 3.00 (s, 3H), 3.02 (s, 3H), 3.70 (m, 1H), 4.10 (m, 1h), 4.20 (m,1H), 4.40 (m, 1H), 4.48 (s, 2H), 4.53 (s, 2H), 4.78 (d, 1H), 6.20 (m,1H), 6.50 (m, 2H), 7.20-7.30 (m, 4H), 7.70 (m, 2H), 8.50 (m, 2H). Massspectrum: (M+H)⁺ =773.

Example 2323(S),6(S)-Bis-(N-(N-methyl-N((2-pyridyl)methyl)amino)carbonyl-valinyl-amino)-4,4-difluoro-5-oxo-2-methyl-7-cyclohexylheptane

Oxidation of the resultant compound from Example 231 using sodiumdichromate in acetic acid provided the desired compound in 55% yield. ¹H NMR (CDCl₃): δ0.85 (d, 6H), 0.88 (d, 6H), 0.96 (m, 12H), 1.10-1.80 (m,13H), 2.00 (m, 1H), 2.25 (m, 2H), 3.00 (s, 3H), 3.02 (s, 3H), 4.00 (t,1H), 4.10 (m, 1H), 4.50 (m, 4H), 5.05 (m, 1H), 6.60 (d, 1H), 7.10-7.30(m, 4H), 7.70 (m, 2H), 8.55 (m, 2H). Mass spectrum: (M+H)⁺ =771.

Example 233 4(S),7(S)-Diamino-2,9-dimethyl-5,5-difluoro-6(R)-hydroxy-decane

Using the procedure described in detail in Examples 189A to 189G, exceptreplacing Boc-L-phenylalaninal with Boc-L-leucinal and replacing benzylmagnesium chloride with isobutyl magnesium chloride provided the desiredcompound. ¹ H NMR (CDCl₃): δ0.95 (m, 12H), 1.25-1.45 (m, 4H), 1.65 (m,1H), 1.85 (m, 1H), 3.20-3.35 (m, 2H), 3.40 (t, 1H), 3.50-3.60 (m, 1H).Mass spectrum: (M+H)⁺ =253.

Example 234 4(S),7(S)-(N-Benzyloxycarbonyl-valinyl)-amino-2,9-dimethyl-5,5-difluoro-6(R)-hydroxy-decane.

Using the resultant compound from Example 233 and coupling tobenzyloxycarbonyl-valine using the carbodiimide procedure provided thedesired compound in 65% yield. 1H NMR (CDCl₃): δ0.90 (m, 24H), 1.45-1.60(m, 2H), 2.15 (m, 12H), 3.90 (m, 2H), 4.25 (m, 2H), 4.60 (m, 1H), 5.10(m, 4H), 5.40 (m, 2H), 6.00 (d, 1H), 6.30 (d, 1H), 7.35 (m, 10H). Massspectrum: (M+H)⁺ =719.

Example 235 4(S),7(S)-Bis-(N-(N-methyl-N-((2-pyridyl)methyl)amino)carbonyl-valinyl-amino)-2,9-dimethyl-5,5-difluoro-6(R)-hydroxydecane

Using the resultant compound from Example 233 and coupling to(N-(-methyl-N-((2-pyriyl)methyl)amino)carbonyl-valine using thecarbodiimide procedure provided the desired compound in 76% yield. ¹ HNMR (CDCl₃): δ0.85 (d, 12H), 0.90 (d, 3H), 0.95 (d, 3H), 0.97 (d, 3H),1.00 (d, 3H), 1.25-1.60 (m, 6H), 2.20 (m, 1H), 2.30 (m, 1H), 2.97 (s,3H), 3.02 (s, 3H), 3.80 (m, 1H), 4.10 (m, 1H), 4.20 (m, 1H), 4.50 (m,4H), 4.85 (d, 1H), 6.10 (m, 1H), 6.30 (d, 1H), 6.50 (d, 1H), 7.15-7.30(m, 4H), 7.70 (m, 2H), 8.52 (m, 2H). Mass spectrum: (M+H)⁺ =747.

Example 236 4(S),7(S)-Bis-(N-(N-methyl)-N-((2-pyridyl)methyl)amino)carbonyl-valinyl-amino)-2,9-dimethyl-5,5-difluoro-6-oxo-decane

Oxidation of the resultant compound from Example 235 using sodiumdichromate in acetic acid provided the desired compound in 50% yield. ¹H NMR (CDCl₃): δ0.82 (d, 3H), 0.85 (d, 3H), 0.87 (d, 3H), 0.90 (d, 3H),0.93 (d, 6H), 0.96 (d, 6H), 1.20-1.60 (m, 6H), 2.20 (m, 2H), 3.00 (s,3H), 3.02 (s, 3H), 4.00 (m, 1H), 4.12 (m, 1H), 4.52 (m, 4H), 4.70-4.75(m, 1H), 4.95 (m, 1H), 6.30 (m, 1H), 6.42 (m, 1H), 6.65 (d, 1H), 6.78(d, 1H), 7.20-7.25 (m, 4H), 7.70 (m, 2H), 8.55 (d, 2H). Mass spectrum:(M+H)⁺ =745.

Example 237 (2S,4S)-2,4-Di-[{N-[N-(2-pyridylmethyl)oxy-carbonyl]-L-tert-Leucyl}amino]-3-hydroxy-1,5-diphenylpentane

A. L-tert-Leucine Methyl ester Hydrochloride

To anhydrous methanol (15 mL) at -20° C. under nitrogen was addedthionyl chloride (4 mL) dropwise. The solution was allowed to warm toroom temperature and then tert-Leucine (4.00 g) was added. The reactionmixture was warmed at 50° C. for 5 hours, re-cooled to -20° C. and thenadditional thionyl chloride (3 mL) was added dropwise. The reactionmixture was heated an additional 2.5 hours at 50° C. and thenconcentrated under reduced pressure and chased twice with methanol (15mL) to afford an amorphous solid. The solid was triturated with ether toafford the title compound in 92% yield. The 300 MHz ¹ H NMR spectrum wasfound to be consistent with the proposed structure. MS (DCI/NH₃) m/e 146(M+H)⁺.

B. N-[N-(2-Pyridylmethyl)oxy-carbonyl]-L-tert-Leucine Methyl ester

To the compound resulting from Example 237A (3.03 g, 16.6 mmol)dissolved in toluene (30 mL) under nitrogen was added triphosgene (5.4g, 1.1 equiv). The reaction mixture was heated at 100° C. for 3 hours,and then the solvent was removed under reduced pressure. The residue waschased twice with toluene (2×15 mL) and dried under vacuum for 1 hour.

To the above isocyanate (2.89 g, 16.88 mmol) dissolved in methylenechloride (20 mL) at room temperature was added 2-pyridylcarbinol (1.79mL, 1.1 equiv). The reaction mixture was stirred at room temperatureovernight and then concentrated under reduced pressure. The residueobtained was chromatographed on silica gel eluting with 1:1 ethylacetate/hexane. The product was re-chromatographed eluting with 2%methanol in methylene chloride to give the title compound. The 300 MHz ¹H NMR spectrum was found to be consistent with the proposed structure.MS (DCI/NH₃) m/e 281 (M+H).

C. N-[N-(2-Pyridylmethyl)oxy-carbonyl]-L-tert-Leucine

To the compound resulting from Example 237B (1.00 g, 3.57 mmol)dissolved in tetrahydrofuran (15 mL) was added 0.5M lithium hydroxide(14.2 mL, 2 equiv). After 5 hours, the reaction mixture was poured intomethylene chloride (25 mL) and water (25 mL). The aqueous phase wasseparated, acidified to pH 4-5 with 1N hydrochloric acid, and extractedwith methylene chloride. The combined organic extracts were dried oversodium sulfate and concentrated under reduced pressure to afford thetitle compound as a white solid (60%). The 300 MHz ¹ H NMR spectrum wasfound to be consistent with the proposed structure. MS (DCI/NH₃) m/e 267(M+H)⁺.

D. N-[N-(2-Pyridylmethyl)oxy-carbonyl]-L-tert-Leucine 4-Nitrophenylester

To the compound resulting from Example 237C (410 mg, 1.54 mmol)dissolved in 1:1 tetrahydrofuran/dimethylformamide was added4-nitrophenol (256 mg, 1.2 equiv) followed by1-ethyl-3-(3'-dimethylamino)-propylcarbodiimide (EDAC) (354 mg, 1.9equiv). The reaction mixture was stirred overnight at room temperatureand then diluted with methylene chloride (50 mL). The solution waswashed with water (35 mL), dried over sodium sulfate, and concentratedunder reduced pressure. The residue obtained was chromatographed onsilica gel eluting with 3:2 hexane/ethyl acetate to afford the titlecompound in 73%. The 300 MHz ¹ H NMR spectrum was found to be consistentwith the proposed structure. MS (DCI/NH₃) m/e 388 (M+H)⁺.

E.(2S,4S)-2,4-Di-[(N-[N-(2-pyridylmethyl)oxy-carbonyl]-L-tert-Leucyl)amino]-3-hydroxy-1,5-diphenylpentane

To the compound resulting from Example 237D (269 mg, 3 equiv) dissolvedin tetrahydrofuran (10 mL) containing triethylamine (0.4 mL, 4 equiv)was added the compound resulting from Example 6F (65 mg). The reactionmixture was heated in an 80° C. oil bath for 6 hours, cooled to roomtemperature, stirred with 3N sodium hydroxide (2 mL) for 1 hour and thenextracted with methylene chloride. The organic phase was washed withwater (35 mL), dried over sodium sulfate and concentrated under reducedpressure to afford crude material. Chromatography on silica gel elutingwith 10% methanol in methylene chloride afforded the title compound(37%). ¹ H NMR (CDCl₃, 300 MHz) δ0.92 (s, 18H), 2.57-3.44 (m, 14H), 3.80(m, 3H), 4.26 (m, 2H), 4.53 (m, 1H), 5.10 (bd, 1H), 5.22 (m, 4H), 5.41(bd, 2H), 5.54 (bd, 1H), 6.35 (bd, 1H), 6.90 (bd, 1H), 7.10-7.35 (m,18H), 7.69 (m, 2H), 8.59 (m, 2H). MS (DCI/NH₃) m/e 767 (M+H)⁺.

Example 238(2S,4S)-2,4-Di-[{N-[N-(2-pyridylmethyl)oxy-carbonyl]-L-Norvalyl}amino]-3-hydroxy-1,5-diphenylpentane

In analogy to the procedure described in Example 237N-[N-(2-Pyridylmethyl)oxy-carbonyl]-L-Norvaline was prepared fromNorvaline. To this compound (84 mg, 0.353 mmol) dissolved in anhydrousdimethylformamide (5 mL) and cooled to 0° C. was added the compoundresulting from Example 6F (75 mg, 0.277 mmol) followed by1-hydroxybenzotriazole (HOBT) (131 mg, 3.5 equiv),1-ethyl-3-(3'-dimethylamino) propylcarbodiimide (EDAC) (160 mg, 3 equiv)and triethylamine (0.1 mL, 3 equiv). The reaction mixture was allowed towarm to room temperature, stirred for 2 days and diluted with methylenechloride (50 mL). The solution was washed with water (50 mL), dried oversodium sulfate, and concentrated under reduced pressure. The residueobtained was chromatographed on silica gel eluting with 10% methanol inmethylene chloride to afford the title compound in 40% yield. ¹ H NMR(CDCl₃, 300 MHz) δ0.79 (t, 3H), 0.90 (t, 3H), 1.00-1.70 (m, 8H), 2.94(m, 2H), 3.18 (m, 2H), 3.70 (m, 1H), 3.88 (m, 2H), 4.16 (m, 1H), 5.00(m, 2H), 5.21 (m, 2H), 5.69 (bd, 1H), 6.35 (bd, 1H), 7.05-7.40 (m, 16H),7.67 (m, 2H), 8.48 (bd, 1H), 8.54 (bd, 1H). MS (DCI/NH₃) m/e 739 (M+H)⁺.

Example 239(2S,4S)-2,4-Di-[N-{2-(N-Benzyloxycarbonyl)amino-2-cyclobutylacetyl}amino]-3-hydroxy-1,5-diphenylpentane A. Cyclobutylacetonitrile

To a solution of cyclobutanemethanol (1.2 g, 0.0139 mol) dissolved inpyridine (5 mL) and cooled to 0° C. was added a catalytic amount ofdimethylaminopyridine (DMAP) and tosyl chloride (2.92 g, 1.1 equiv). Thereaction mixture was allowed to warm to room temperature and stirred for4 hours. The reaction mixture was taken up in methylene chloride (50mL), washed with water (50 mL), dried over sodium sulfate, andconcentrated under reduced pressure to afford the tosylate (92%).

To the tosylate (14.3 g, 59.5 mmol) dissolved in dimethyl sulfoxide (20mL) was added sodium cyanide (3.2 g, 1.1 equiv). The reaction mixturewas heated at 90° C. for 2 hours, cooled to room temperature, dilutedwith ethyl acetate (300 mL), washed with H₂ O (3×100 mL), dried oversodium sulfate, and concentrated under reduced pressure to afford ayellow liquid. Vacuum distillation afforded the title compound (60%).b.p. 62° C.

B. Cyclobutylacetic acid

The compound resulting from Example 239A (0.8 g, 8.41 mmol) wasdissolved in 50% aqueous sodium hydroxide (4 mL) and warmed at refluxfor 4 hours. After cooling to room temperature, the reaction mixture wasacidified to pH 2-3 with 1N hydrochloric acid and extracted with ethylacetate (100 mL). The organic phase was washed with water (3×100 mL),dried over sodium sulfate and concentrated under reduced pressure.

C. N-Cyclobutylacetyl-4-benzyl-2-oxazolidinone

To the compound resulting from Example 239B (0.95 g, 8.32 mmol)dissolved in anhydrous tetrahydrofuran (8 mL) and cooled at -78° C. wasadded triethylamine (1.5 mL, 1.3 equiv) followed by pivaloyl chloride(1.12 mL, 1.1 equiv). The reation mixture was stirred at -78° C. for 15minutes and room temperature for 1 hour and then cooled to -78° C.again.

To (S)(-)-4-benzyl-2-oxazolidinone (2.65 g, 1.8 equiv) dissolved intetrahydrofuran (25 mL) at -78° C. was added 2.5M butyl lithium (5.98mL, 1.8 equiv). After 5 minutes, this solution was cannulated into theabove solution. The reaction mixture was allowed to come to roomtemperature and stirred for 2 hours. The reaction mixture was dilutedwith chloroform (150 mL), washed with 10% sodium bisulfite (100 mL),dried over sodium sulfate, and concentrated under reduced pressure. Theresidue obtained was chromatographed on silica gel eluting with 3:2hexane/ethyl acetate to afford the title compound in 58% yield.

D. N-[Cyclobutyl-2-azidoacetyl]-4-benzyl-2-oxazolidinone

To the compound re-suiting from Example 239C (287 mg, 1.05 mmol)dissolved in anhydrous tetrahydrofuran (10 mL) and cooled to -78° C.under nitrogen was added potassium hexamethyldisilazide (0.5M intoluene, 2.1 mL, 1 equiv). After 15 minutes at -78° C. 2 46-triisopropylbenzenesulfonyl azide (Trisylazide) (389 mg, 1.2 equiv) intetrahydrofuran (5 mL) at -78° C. was cannulated into the reactionmixture. After 2 minutes at -78° C., glacial acetic acid (0.18 mL, 3equiv) was added and the temperature was allowed to rise to 30° C. withthe use of a water bath. After 1.5 hours, methylene chloride (100 mL)was added; the solution was washed with water (3×50 mL), dried oversodium sulfate, and concentrated under reduced pressure. The residueobtained was chromatographed on silica gel eluting with 3:2 hexane/ethylacetate to afford the title compound in 77% yield.

E. N-[Cyclobutyl-2-(Cbz-amino)acetyl]-4-benzyl-2-oxazolidinone

To the compound resulting from Example 239D (0.44 g, 1.4 mmol) dissolvedin 10:8:1 methanol, tetrahydrofuran and trifluoroacetic acid was added10% palladium on carbon (100 mg). The reaction mixture was placed underhydrogen for three hours. The catalyst was removed by filtration throughCelite, washed with methanol (10 mL), and the filtrate concentratedunder reduced pressure. Methylene chloride (10 mL) was added to theresidue obtained and the mixture was cooled to 0° C. Benzylchloroformate(0.38 mL, 2 equiv) was added followed by triethylamine (0.3 mL, 3equiv). The reaction mixture was allowed to warm to room temperature andstirred overnight. Sodium bisulfite was added and the reaction mixturewas extracted with methylene chloride (100 mL). The combined organicextracts were washed with water (3×20 mL), dried over sodium sulfate,and concentrated under reduced pressure. The residue obtained waschromatographed on silica gel eluting with 1:3 ethyl acetate/hexane toafford the title compound in 53% yield.

F. 2-Cyclobutyl-2-(Cbz-amino) acetic acid

To the compound resulting from Example 239E (170 mg, 0.402 mmol)dissolved in 1:3 water/tetrahydrofuran (4 mL) cooled to 0° C. was addedlithium hydroxide (34 mg, 2 equiv). After 40 minutes, the reactionmixture was added to aqueous sodium chloride (20 mL) and then washedwith methylene chloride (3×30 mL). The aqueous phase was acidified to pH2 with 1N hydrochloric acid and then extracted with ethyl acetate (4×30mL). The combined organic extracts were dried over sodium sulfate andconcentrated under reduced pressure to afford the title compound as awhite solid (71%).

G.(2S,4S)-2,4-Di-[N-{2-(N-Benzyloxycarbonyl)amino-2-cyclobutylacetyl}amino]-3-hydroxy-1,5-diphenylpentane

The compound resulting from Example 239F (80 mg, 0.34 mmol) was coupledwith the compound resulting from Example 6F (68 mg, 0.252 mmol) by theprocedure described in Example 238 to give crude material.Chromatography on silica gel eluting with 3% methanol in methylenechloride afforded the title compound (70 mg). ¹ H NMR (CDCl₃, 300 MHz)δ1.46 (m, 14H), 2.32 (m, 1H), 2.60-3.30 (m, 6H), 3.42 (bs, 1H), 3.70(bs, 2H), 4.07 (m, 1H), 4.72 (m, 1H), 4.83-5.05 (m, 4H), 5.20 (bs, 1H),5.52 (bs, 1H), 6.15 (bs, 1H), 7.10-7.38 (m, 20H). MS (DCI/NH₃) m/e 761(M+H)⁺, 778 (M+H+NH₃)⁺.

Example 240 (2S,4S)-2,4-Di-[N-{2-(N-Benzyloxycarbonyl)amino-2-cyclopentylacetyl}amino]-3-hydroxy-1,5-diphenylpentane

2-Cyclopentyl-2-(Cbz-amino)acetic acid was prepared in analogy to theprocedure described in Example 239 starting from cyclopentylacetic acid.This compound (135 mg) was coupled with the compound resulting fromExample 6F (107 mg) by the procedure described in Example 238 to affordcrude product. Chromatography on silica gel eluting with 3% methanol inmethylene chloride afforded the title compound (110 mg). ¹ H NMR(DMSO-d₆, 300 MHz) δ1.02-1.66 (m, 18H), 1.96 (m, 2H), 2.76 (m, 3H), 2.96(m, 1H), 3.52 (m, 1H), 3.77 (m, 4H), 4.09 (m, 1H), 5.01 (d, 4H), 5.34(bd, 1H), 7.00-7.47 (m, 22H). MS (DCI/NH₃) m/e 789 (M+H)⁺.

Example 241 (2S,4S)-2,4-Di-[N-{2-(N-Benzyloxycarbonyl)amino-2-cyclopropylacetyl}amino]-3-hydroxy-1,5-diphenylpentane

2-Cyclopropyl-2-(Cbz-amino)acetic acid was prepared in analogy to theprocedure described in Example 239 starting from cyclopropylacetic acid.This compound (230 mg, 0.923 mmol) was coupled with the compoundresulting from Example 6F (208 mg) by the procedure described in Example238 to afford crude product. Chromatography on silica gel eluting with5% methanol in methylene chloride afforded the title compound (220 mg)as a white solid. ¹ H NMR (CDCl₃, 300 MHz) δ0.10-0.66 (m, 10H), 0.91 (m,1H), 1.13 (m, 1H), 2.90-3.30 (m, 8H) 3.57 (bs, 2H), 3.95 (bs, 1H),4.40-4.93 (m, 4H), 5.30 (m, 2H), 5.55 (bd, 1H), 6.49 (m, 1H), 7.10-7.37(m, 20H). MS (DCI/NH₃) m/e 733 (M+H)⁺.

Example 242 (2S,4S)-2,4-Di-[N-{N-Boc-(Thiazol-2-yl)Alanyl}amino]-3-hydroxy-1,5-diphenylpentane

N-Boc-(Thiazol-2-yl)Alanine (264 mg) was coupled with the compoundresulting from Example 6F by the procedure described in Example 238 toafford crude material. Chromatography on silica gel eluting with 7%methanol in methylene chloride afforded the title compound as a whitesolid (58%). ¹ H NMR (CDCl₃, 300 MHz) δ1.22 (s, 9H), 1.40 (s, 9H),2.80-3.50 (m, 11H), 3.64 (bs, 1H), 3.77 (bs, 1H), 4.21 (bs, 1H), 4.64(bs, 1H), 5.68 (m, 1H), 5.97 (m, 1H), 6.07 (bs, 1H), 6.89-7.33 (m, 14H),7.48 (m, 1H), 7.77 (bs, 1H), 8.61 (bs, 1H). MS (DCI/NH₃) m/e 779 (M+H)⁺.

Example 243 (2S,5R)-N-[2-(N-Cbz-Valyl)amino-3-phenyl-1-propyl]-N-hydroxy-Phenylalanyl-ValylN-(2-Hydroxyethyl)amide A. N-Boc-Phenylalaninal

To dimethyl sulfoxide (2.82 mL, 39.8 mmol) dissolved in anhydrousmethylene chloride (5 mL) and cooled to -78° C. was added dropwiseoxalyl chloride (2.6 mL, 1.5 equiv). After 10 minutes at -78° C.,N-Boc-Phenylalaninol (5.00 g, 19.9 mmol) dissolved in anhydrousmethylene chloride (75 mL) was cannulated into the reaction mixture.After 15 minutes at -78° C., the reaction was stirred for 2 minutes at0° C. and then cooled again to -78° C. Triethylamine (11.9 mL, 4.3equiv) was added dropwise. After 25 minutes, the reaction was quenchedwith cooled 10% citric acid (15 mL) and then diluted with additional 10%citric acid (75 mL). Ether (300 mL) was added and the solution waswashed with water (5×100 mL), brine, water (5×100 mL), and brine, driedover sodium sulfate, and concentrated under reduced pressure to affordthe title compound (4.22 g).

B. (2S,5R)-N-[2-(N-Boc-amino)-3-phenyl-1-propyl]-Phenylalanyl Methylester

To the compound resulting from Example 243A (4.22 g, 16.9 mmol)dissolved in isopropyl alcohol (60 mL) at 0° C. was added phenylalaninemethyl ester hydrochloride (3.94 g, 1.08 equiv) followed by sodiumacetate (2.91 g, 2.1 equiv). After stirring 30 minutes at 0° C. thereaction mixture was cooled to -35° C. and treated with sodiumcyanoborohydride (1.33 g, 1.25 equiv). The reaction mixture was allowedto warm to room temperature and stirred overnight. The solvent wasremoved under reduced pressure and the solid obtained dissolved in ethylacetate (300 mL). The solution was washed with saturated sodiumbicarbonate (2×100 mL), water (100: mL), and brine (100 mL), dried oversodium sulfate, and concentrated under reduced pressure. The crudeproduct was chromatographed on silica gel eluting with 1:4 ethylacetate/methylene chloride to afford the title product. The 300 MHz ¹ HNMR spectrum was found to be consistent with the proposed structure. MS(DCI/NH₃) m/e 413 (M+H)⁺.

C. 2S,5R)-N-[2-(N-Boc-amino)-3-phenyl-1-propyl]-N-hydroxy-PhenylalanylMethyl ester

To the compound resulting from Example 243B (325 mg, 0.788 mmol)dissolved in acetone (3 mL) at -40° C. was added dropwise 0.09Mdimethyldioxirane (3 equiv). After 1 hour at -40° C., the reaction waswarmed to 0° C. and stirred for 1 hour. The reaction was warmed to roomtemperature and additional 0.09M dimethyldioxirane (2 equiv) was added.After 1 hour, the solvent was removed under reduced pressure. Theresidue obtained was chromatographed on silica gel eluting with 1:9ethyl acetate in methylene chloride to afford the title compound as awhite solid (53%). ¹ H NMR (CDCl₃, 300 MHz) δ1.43 (s, 9H), 2.50 (m, 1H),2.79 (m, 2H), 2.98 (d of d, 1H), 3.10 (d, 2H), 3.49 (t, 1H), 3.64 (s,3H), 4.12 (m, 1H), 4.74 (bd, 1H), 6.61 (bs, 1H), 7.04 (bd, 1H), 7.24 (m,10H). MS (DCI/NH₃) m/e 429 (M+H)⁺.

D. (2S, 5R)-N-[2-(N-Boc-amino)-3-phenyl-1-propyl]Phenylalanine

To the compound resulting from Example 243B (335 mg, 8.12 mmol)dissolved in 2:1 tetrahydrofuran/water (15 mL) was added lithiumhydroxide monohydrate (1.5 equiv). After 1.74 hours, 1N hydrochloricacid (1.5 equiv) was added and the solvent removed under reducedpressure to afford the title compound as a white solid (73%). MS(DCI/NH₃) m/e 399 (M+H)⁺.

E. (2S, 5R)-N-[2-(N-Boc-amino)-3-phenyl-1-propyl]Phenylalanyl-ValylBenzyl ester

The compound resulting from Example 243D (223 mg, 0.819 mmol) wascoupled with Valine benzyl ester methanesulfonate salt (257 mg, 0.6766mmol) by the procedure described in Example 238 to afford crudematerial. Chromatography on silica gel eluting with 2% methanol inmethylene chloride afforded the title compound as a white solid (166 mg,35%).

F. (2S,5R)-N-[2-(N-Boc-amino)-3-phenyl-1-propyl]-N-hydroxy-Phenylalanyl-ValylBenzyl ester

The compound resulting from Example 243F (166 mg) was reacted withdimethyldioxirane by the procedure described in Example 243C to givecrude material. Chromatography on silica gel eluting with 2% methanol inmethylene chloride afforded the title compound as a white solid (63%). ¹H NMR (CDCl₃, 300 MHz) δ0.85 (m, 6H), 0.95 (m, 1H), 1.40 (s, 9H), 2.19(m, 1H), 2.46 (m, 1H), 2.62-2.90 (m, 3H), 3.10 (m, 4H), 3.49 (m, 1H),4.20 (bs, 1H), 4.54 (m, 2H), 5.15 (m, 3H), 7.09 (bd, 1H), 7.10-7.46 (m,15H). MS (DCI/NH₃) m/e 604 (M+H)⁺.

G. (2S, 5R)-N-[2-Amino-3-phenyl-1-propyl]-Phenylalanyl-Valyl Benzylester

To the compound resulting from Example 243E (528 mg, 0.99 mmol)dissolved in dioxane (20 mL) and cooled to 0° C. was added dropwise 4.4Mhydrochloric acid in dioxane (0.56 mL). The reaction mixture was allowedto warm to room temperature and then additional 4.4M hydrochloric acidin dioxane (10 mL) was added. After 30 minutes, the reaction was workedup to afford the title compound in 72% yield.

H. (2S,5R)-N-[2-(N-Cbz-Valyl)amino-3.phenyl-1-propyl]Phenylalanyl-ValylBenzyl ester

The compound resulting from Example 243G (100 mg, 0.2046 mmol) wascoupled with N-Cbz-L-Valine (62 mg, 1.2 equiv) by the proceduredescribed in Example 238 to give crude material. Chromatography onsilica gel eluting with 2% methanol in methylene chloride afforded thetitle compound in 53% yield.

I.(2S,5R)-N-[2-(N-Cbz-Valyl)amino-3-phenyl-1-propyl]-N-hydroxy-Phenylalanyl-ValylBenzyl ester

The compound resulting from Example 243H (50 mg, 0.07 mmol) was reactedwith dimethyldioxirane by the procedure described in Example 243C toafford crude material. Chromatography on silica gel eluting with 5%methanol in methylene chloride afforded the title compound (74%). ¹ HNMR (CDCl₃, 300 MHz) δ0.65 (m, 8H), 2.10 (m, 1H), 2.21 (m, 1H), 2.42 (m,1H), 2.60 (m, 1H), 2.80 (m, 1H), 3.05 (m, 2H), 3.40 (m, 1H), 3.72 (m,1H), 4.40 (m, 1H), 4.55 (m, 1H), 4.95 (m, 1H), 5.00-5.24 (m, 3H), 6.13(m, 1H), 7.05 (m, 1H), 7.14-7.49 (m, 15H). MS (DCI/NH₃) m/e 737 (M)⁺.

J. (2S, 5R)-N-[2-(N-Cbz-Valyl)amino-3-phenyl-1-propyl]Phenylalanyl-ValylN-(2-Hydroxyethyl)amide

The compound resulting from Example 243H (232 mg, 0.3213 mmol) washydrolyzed by the procedure described in Example 239F and trituratedwith acetonitrile to give the carboxylic acid as a white solid (88%).

The above carboxylic acid (203 mg, 0.3213 mmol) was coupled withethanolamine (15.9 mg, 0.2678 mmol) by the procedure described inExample 238 to give crude material. Chromatography on silica gel elutingwith 8% methanol in methylene chloride afforded the title compound as awhite solid (51%). ¹ H NMR (CDCl₃, 300 MHz) δ0.70-0.97 (m, 12H),2.60-2.94 (m, 4H), 3.64 (m, 2H), 4.00 (m, 2H), 5.10 (m, 2H), 5.52 (bd,1H), 6.78 (bd, 1H), 7.00 (m, 1H), 7.10-7.40 (m, 15H), 7.96 (bd, 1H). MS(DCI/NH₃) m/e 674 (M+H)⁺.

K.(2S,5R)-N-[2-(N-Cbz-Valyl)amino-3-phenyl-1-propyl]-N-hydroxy-Phenylalanyl-ValylN-(2-Hydroxyethyl)amide

The compound resulting from Example 243J (110 mg, 0.163 mmol) wasreacted with dimethyldioxirane by the procedure described in Example243C to give crude material. Chromatography on silica gel eluting with8% methanol in methylene chloride afforded the title compound as a whitesolid (50%). This compound was re-chromatographed on silica gel elutingwith 6% methanol in methylene chloride. ¹ H NMR (CDCl₃, 300 MHz)δ0.70-1.00 (m, 12H), 2.11 (m, 2H), 2.31 (m, 1H), 2.55-3.19 (m, 6H), 3.29(m, 2H), 3.64 (m, 4H), 3.84 (m, 1H), 4.26 (m, 1H), 4.41 (m, 1H), 5.10(m, 2H), 6.21 (m, 1H), 6.48 (m, 1H), 6.82 (m, 1H), 6.90-7.40 (m, 15H).MS (DCI/NH₃) m/e 690 (M+H)⁺.

Example 244 (2S, 3R,4S)-2,4-Di-{N-[(2-pyridylmethyl)oxycarbonyl]-L-Valyl}amino-3-hydroxy-1-phenyl-5-(4-methylphenyl)pentane A. 2-Boc-Amino-1-phenyl-5-(4-methylphenyl) pent-3-ene

To a solution of anhydrous copper(I) cyanide (0.29 g, 3.2 mmol)dissolved in anhydrous tetrahydrofuran (100 mL) under nitrogen andcooled in a dry ice/acetone bath was added a solution ofp-tolylmagnesium bromide (1M solution in ether) (33 mL, 33 mmol) viasyringe. The dry ice/acetone bath was removed and replaced with a coldwater bath. When the internal temperature reached -1° C., the mixturewas cooled in a dry ice/acetone bath and a solution of2-Boc-amino-3-methanesulfonyloxy-1-phenyl-pent-4-ene (3.58 g, 10.5 mmol)dissolved in tetrahydrofuran (20 mL) was added via syringe. The mixturewas stirred at -70° C. for 15 minutes. The bath was removed, and thesolution was immediately treated with saturated ammonium chloridesolution (20 mL) followed by ether (60 mL). As the mixture warmed, 1Nammonium hydroxide (20 mL) was added. The mixture was stirred at roomtemperature overnight and then extracted with ether (100 mL). Theorganic phase washed with saturated sodium chloride solution, dried overmagnesium sulfate, and concentrated under reduced pressure to afford thecrude compound as a semi-solid residue (3.77 g). Chromatography onsilica gel eluting with hexane and 5% ethyl acetate in hexane affordedthe title product as a white solid (1.6607 g, 45%). m.p. 92°-93° C.

B. 2-Boc-Amino-3,4-epoxy-1-phenyl-5-(4-methylphenyl) pentane

To a suspension of the product resulting from Example 244A (1.63 g, 4.64mmol) and sodium bicarbonate (2.0 g, 23.8 mmol) in methylene chloride(26.7 mL) and cooled in an ice bath was added m-chloroperbenzoic acid(50%, 3.20 g, 9.27 mmol). When the reaction mixture became a thick mass,additional methylene chloride (7 mL) was added and stirring wascontinued at ice bath temperature for 7 hours and then the reactionmixture was placed in the refrigerator for two days. The reactionmixture was stirred in ether (40 mL) and 10% aqueous sodium thiosulfatepentahydrate (53 mL) for 2.5 hours. The layers were separated and theorganic layer washed with 2N sodium hydroxide (27 mL); additional ether(75 mL) was added. The organic layer was washed with water (27 mL) andbrine (27 mL). The combined aqueous layers were back-extracted withether (3×50 mL) and these combined ether extracted were washed withwater (50 mL) and brine (50 mL). The combined organic extracts weredried over magnesium sulfate and concentrated under reduced pressure toafford crude material. Chromatography on silica gel eluting with 1:5ethyl acetate/hexane afforded an oil which solidified on standing togive the title product (1.158 g, 68%).

C. 2-Boc-Amino-4-azido-3-hydroxy-1-phenyl-5-(4-methylphenyl)pentane

A solution of the product resulting from Example 244B (1.1464 g, 3.12mmol), lithium azide (844.9 mg, 17.25 mmol), and ammonium chloride(208.8 mg, 3.90 mmol) in dimethylformamide (10 mL) and water (1.0 mL)was stirred and warmed at 70° C. under nitrogen for 32 hours and letstand for two days at room temperature. The reaction mixture waspartitioned between 1:1 ethyl acetate/hexane (120 mL) and water (96 mL).The aqueous layer was back-extracted with 1:1 ether/hexane (2×60 mL).The combined organic extracts were washed with water (50 mL) and brine(25 mL), dried over magnesium sulfate, and concentrated under reducedpressure. The residue obtained was chromatographed on silica gel elutingwith a gradient of ethyl acetate/hexane of 1:9 going to 1:5 to affordthe title compound (1.0674 g, 83%). m.p. 110° C.

D. 2-Boc-Amino-4-amino-3-hydroxy-1-phenyl-5-(4-methylphenyl)pentane

To a suspension of 10% palladium on carbon (206 mg) in methanol (5.8 mL)was added ammonium formate (1.14 g, 18.1 mmol) with stirring undernitrogen. After 10 minutes, the compound resulting from Example 244C(1.05 g, 2.56 mmol) dissolved in methanol (9.2 mL plus 1.0 mL wash) wasadded. After 2.25 hours, the reaction mixture was filtered through aMillipore filter (EH type). The filtrate was concentrated under reducedpressure to approximately 6 mL, sodium chloride was added, and themixture was extracted with chloroform (3×25 mL). The combined organicextracts were dried over magnesium sulfate and concentrated underreduced pressure to afford crude material (942 mg). Chromatography onsilica gel eluting with 1:20 methanol/hexane afforded the title compound(698 mg).

E. 2,4-Diamino-3-hydroxy-1-phenyl-5-(4-methylphenyl) pentane

A solution of the compound resulting from Example 244D (691 mg, 1.797mmol) in 4M hydrochloric acid in dioxane (10 mL) was stirred at roomtemperature for 2 hours and then concentrated under reduced pressure.The residue obtained was taken up in a mixture consisting of chloroform(100 mL), methanol (3.32 mL), 5% sodium bicarbonate solution (6.65 m/L),and 3.0M sodium hydroxide solution (6.65 mL). The aqueous layer wasextracted with chloroform (50 mL). The combined organic extracts weredried over magnesium sulfate and concentrated under reduced pressure toafford the title compound as a white solid (467 mg, 91%). m.p. 126°-128°C.

F.(2S,3R,4S)-2,4-Di-{N-[(2-pyridylmethyl)oxycarbonyl]-L-Valyl}amino-3-hydroxy-1-phenyl-5-(4-methylphenyl)pentane

Triethylamine (0.15 mL, 1.052 mmol) was added to a stirred solution ofthe compound resulting from Example 244E (74.8 mg, 0.263 mmol) andN-[(2-pyridylmethyl)oxycarbonyl]Valine 4-nitrophenyl ester (294.5 mg,0.789 mmol) dissolved in anhydrous tetrahydrofuran (7.5 mL). Thereaction mixture was stirred at reflux under nitrogen for 5 hours andthen at room temperature overnight. A solution of 3M sodium hydroxide(1.5 mL) was added, and the reaction mixture was stirred at roomtemperature for 2 hours, diluted with chloroform (100 mL), washed with0.5M sodium hydroxide (4×15 mL) and brine (15 mL), dried over magnesiumsulfate, and concentrated under reduced pressure to afford crudematerial. Chromatography on silica gel eluting with 1:30 methanol inmethylene chloride afforded the title compound (106 mg, 54%). m.p.195°-198° C. MS (DCI/NH₃) m/e 753 (M+H)⁺.

Example 245 (2S, 3R,4S)-2,4-Di-{N-[(2-pyridylmethyl)oxycarbonyl]-L-Valyl}amino-3-hydroxy-1-phenyl-5-(2-methylphenyl)pentane

2,4-Diamino-3-hydroxy-1-phenyl-5-(2-methylphenyl) pentane was preparedin analogy to Example 244E using the ortho- rather than para-substitutedGrignard reagent. This compound (149.6 mg) was coupled withN-[(2-pyridylmethyl) oxycarbonyl]-Valine 4-nitrophenyl ester (589 mg) bythe procedure described in Example 244F to give the title compound (172mg). ¹ H NMR (CDCl₃, 300 MHz) δ0.57-1.02 (M, 12H), 1.98 (M, 1H), 2.25(M, 2H), 2.29 (S, 3H), 2.77 (M, 1H), 3.10 (BD, 2H), 3.35 (M, 1H), 3.70(M, 3H), 4.02 (M, 2H), 5.10 (M, 6H), 5.72 (BD, 1H), 6.30 (BD, 1H),7.00-7.30 (M, 18H), 7.66 (M, 2H), 8.55 (M, 2H). MS (FAB) m/e 753 (M+H)⁺.

Example 246 (2S,3R, 4S),2,4-Di-{N-[(2-pyridylmethyl)oxycarbonyl1-L-Valyl}amino-3-hydroxy-1-phenyl-5-(3-methylphenyl) pentane

2,4-Diamino-3-hydroxy-1-phenyl-5-(3-methylphenyl) pentane was preparedin analogy to Example 244E using the meta- rather than para-substitutedGrignard reagent. This compound (149.6 mg) was coupled withN-[(2-pyridylmethyl)oxycarbonyl]-Valine 4-nitrophenyl ester (589 mg) bythe procedure described in Example 244F to give the title compound (136mg). ¹ H NMR (CDCl₃, 300 MHz) δ0.68 (d, 3H), 0.77 (d, 3H), 0.90 (m, 6H),2.01 (m, 1H), 2.25 (s, 3H), 2.29 (m, 2H), 2.95 (m, 3H), 3.15 (m, 2H),3.68 (m, 2H), 3.85 (m, 3H), 4.10 (m, 1H), 5.14 (m, 5H), 5.33-(m, 1H),5.87 (bs, 1H), 6.40 (bs, 1H), 6.90-7.40 (m, 18H), 7.74 (m, 2H), 8.57 (m,2H). MS (FAB) m/e 753 (M+H)⁺.

Example 247 (2S,3R,4S)-2,4-Di-{N-[(3-pyridylmethyl)oxycarbonyl]-L-Valyl}amino-3-hydroxy-1-phenyl-5-(4-fluorophenyl)pentane

2,4-Diamino-3-hydroxy-1-phenyl-5-(4-fluorophenyl) pentane was preparedin analogy to Example 244E using the para-fluoro rather than para-methylsubstituted Grignard reagent. This compound (152.8 mg) was coupled withN-[(2-pyridylmethyl) oxycarbonyl]-Valine 4-nitrophenyl ester (589 mg) bythe procedure described in Example 244F to give the title compound (186mg). ¹ H NMR (CDCl₃, 300 MHz) δ0.67 (d, 3H), 0.75 (d, 3H), 0.89 (m, 6H),2.00 (m, 1H), 2.26 (m, 1H), 2.85 (m, 1H), 3.10 (m, 4H), 3.55-4.10 (m,6H), 5.04-5.37 (m, 6H), 5.66 (bd, 1H), 6.27 (bd, 1H), 6.90 (m, 2H),7.05-7.35 (m, 16H), 7.67 (m, 2H), 8.54 (m, 2H). MS (DCI/NH₃) m/e 757(M+H)⁺.

Example 248 (2S,3R,4S)-2,4-Di-{N-[N-methyl-N-(2-pyridylmethyl)amino(thiocarbonyl)]-L-Valyl}amino-3-hydroxy-1,5-diphenylpentane A. (1-Carbomethoxisobutyl)isothiocyanate

To a stirred suspension of Valine methyl ester hydrochloride (1.0 g,5.96 mmol) in chloroform (10 mL) cooled to -20° C. was addedthiophosgene (0.48 mL, 6.26 mmol) followed by the dropwise addion oftriethylamine (2.49 mL, 17.88 mmol) in chloroform (10 mL). The reactionmixture was stirred at -20° C. for 15 minutes and then 0.1M hydrochloricacid (10 mL) was added. The organic layer was washed with water (4×5mL), dried over magnesium sulfate, and concentrated under reducedpressure to afford the title compound (1.01 g).

B. N-[N-Methyl-N-(2-pyridylmethyl)amino-(thiocarbonyl)]Valine Methylester

To a suspension of N-methyl-N-(2-pyridylmethyl)amine dihydrochloride(809.9 mg, 4.15 mmol) in methylene chloride (40 mL) was added4-methylmorpholine (1.14 mL, 10.37 mmol) followed by a solution of thecompound resulting from Example 248A (1.01 g) in methylene chloride (10mL). The reaction mixture was stirred at room temperature overnight. Thereaction mixture was washed with water (3×15 mL), dried over magnesiumsulfate, and concentrated under reduced pressure to afford crudematerial (1.54 g). Chromatography on silica gel eluting with 1:7 ethylacetate in methylene chloride afforded the title compound (1.2275 g,100%).

C. N-[N-Methyl-N-(2-pyridylmethyl)amino-(thiocarbonyl)]Valine

To a solution of the compound resulting from Example 248B (1.22 g, 4.13mmol) dissolved in tetrahydrofuran (15 mL) and cooled in an ice bath wasadded 0.5M lithium hydroxide (16.5 mL, 2 equiv). The reaction mixturewas stirred in the ice bath for 1.5 hours and then at room temperaturefor 3 hours. Water (25 mL) was added and the mixture was washed withmethylene chloride (25 mL). The aqueous layer was separated, acidifiedto pH 3-4 with 1N hydrochloric acid (8.25 mL), and extracted with ethylacetate (5×25 mL). The combined organic extracts were dried overmagnesium sulfate and concentrated under reduced pressure to afford thetitle compound (929 mg).

D.(2S,4S)-2,4-Di-{N-[N-methyl-N-(2-pyridylmethyl)amino(thiocarbonyl)]-L-Valyl}amino-3-hydroxy-1,5-diphenylpentane

To a stirred solution of the resultant compound of Example 6F (54 mg,0.2 mmol), the compound resulting from Example 248C (135.1 mg, 0.48mmol), 1-ethyl-3-(3'-dimethylamino)-propylcarbodiimide (EDAC) (191.7 mg,1 mmol) and 1-hydroxybenzotriazole hydrate (HOBT) (189.2 mg, 1.4 mmol)in anhydrous dimethylformamide (2.5 mL) under nitrogen and cooled in anice bath was added via syringe triethylamine (0.14 mL, 1 mmol). Themixture was stirred in the ice bath allowing the temperature togradually rise to room temperature over 2 hours. After 24 hours, themixture was concentrated under reduced pressure and the residue obtainedtriturated with water (20 mL) and extracted with ethyl acetate (4×20mL). The combined organic extracts were dried over magnesium sulfate andconcentrated under reduced pressure to afford crude material (250 mg).Chromatography on silica gel eluting wtih 1:40 methanol in methylenechloride afforded the title compound (49.7 mg, 31%) as an amorphoussolid. ¹ H NMR (CDCl₃, 300 MHz) δ0.69-1.10 (m, 12H), 1.67 (m, 2H), 2.07(m, 1H), 2.40 (m, 1H), 3.07 (m, 1H), 3.23 (m, 2H), 3.37 (s, 3H),3.60-3.94 (m, 2H), 4.06 (m, 1H), 4.37-4.56 (m, 2H), 4.80 (m, 2H), 4.98(m, 1H), 7.00 (bd, 1H), 7.08-7.48 (m, 15H), 7.56-7.83 (m, 3H), 8.15 (m,1H), 8.30 (m, 1H), 8.54 (m, 2H). MS (FAB) m/e 797 molecular ion.

Example 249 (2S, 3R, 4R,5S)-2,4-Di-{N-[N-methyl-N-(2-pyridylmethyl]amino-(thiocarbonyl)]-L-Valyl}amino-3,4-dihydroxy-1,6-diphenylhexane A. N-[N-Methyl-N-(2-pyridylmethyl)amino-(thiocarbonyl)]Valine4-Nitrophenyl ester

To a solution of the compound resulting from Example 248C (281.3 mg, 1mmol) and 4-nitrophenol (153 mg, 1.1 mmol) dissolved in anhydrousmethylene chloride (14 mL) and cooled in an ice bath was addeddicyclohexylcarbodiimide (DCC) (227 mg, 1.1 mmol). The reaction mixturewas stirred in the ice bath for 2 hours and then at room temperature for3 hours. The by-product was removed by filtration and the filtrateconcentrated under reduced pressure to afford the title compound.

B. (2S, 3R, 4R,5S)-2,4-Di-{N-[N-methyl-N-(2-pyridylmethyl)amino-(thiocarbonyl)]-L-Valyl}amino-3,4-dihydroxy-1,6-diphenylhexane

The compound resulting from Example 249A (0.8 mmol) and the compoundresulting from Example 4A (132 mg, 0.4 mmol) were stirred in anhydrousdimethylformamide (4 mL) at room temperature for 16 hours. The reactionmixture was diluted with ethyl acetate (200 mL) and washed with 5%sodium bicarbonate solution (3×30 mL). The organic phase was dried overmagnesium sulfate and concentrated under reduced pressure to affordcrude material (683.4 mg). Chromatography on silica gel eluting with1:30 methanol in methylene chloride afforded the title compound (77.2mg). ¹ H NMR (CDCl₃, 300 MHz) δ0.71 (d, 3H), 0.81 (d, d of d, 9H), 0.90(d of d, 6H), 2.05 (m, 1H), 2.24 (m, 2H), 2.80-2.95 (m, 4H), 3.30-3.36(2s, 6H), 3.58 (m, 2H), 3.75 (m, 1H), 3.87 (m, 1H), 4.31 (m, 2H),4.58-4.85 (m, 6H), 6.39 (m, 2H), 7.05-7.35 (m, 16H), 7.64-7.80 (m, 2H),8.47 (m, 2H). MS (FAB) m/e 827 (M+H), 849 (M+Na)⁺.

Example 250 (2S, 3R,4S)-2,4-Di-{N-Cbz-L-Histidyl}amino-3-hydroxy-1-phenyl-5-(4-methylphenyl)pentane

To a stirred solution of the compound resulting from Example 244E (85.3mg, 0.3 mmol), HOBT (121.6 mg, 0.9 mmol), and EDAC (172.5 mg, 0.9 mmol)dissolved in dimethylformamide (5 mL) and cooled in an ice bath wasadded 4-methylmorpholine (NMM) (0.099 mL, 0.9 mmol) via syringe. Themixture was stirred in the ice bath and was allowed to gradually warm toroom temperature and stirred at room temperature for 24 hours. Themixture was concentrated under reduced pressure and the residue obtainedtriturated with water (20 mL) and extracted with ethyl acetate (4×20mL). The combined organic extracts were dried over magnesium sulfate andconcentrated under reduced pressure to afford crude material.Chromatography on silica gel eluting with 10-20% methanol in methylenechloride afforded the title compound (48 mg, 19%). ¹ H NMR (DMSO-d₆, 300MHz) δ2.50 (s, 3H), 2.55-2.92 (m, 4H), 3.00-3.87 (m, 4H), 4.00-4.25 (m,2H), 4.97 (m, 2H), 6.84 (d, 1H), 6.90-7.45 (m, 14H), 7.50 (m, 1H), 7.79(m, 2H). MS (FAB) m/e 827 (M+H)⁺, 849 (M+Na)⁺.

Example 2512,5-Di-{N-Bromoacetyl-(L)-Valyl}amino-3,4-dihydroxy-1,6-diphenyl hexane

2,5-Di-{(L)-Valyl}amino-3,4-dihydroxy-1,6-diphenyl hexane (1.00 g, 2mmol) was dissolved in dimethylformamide (75 mL) with warming and thencooled to room temperature under nitrogen. Triethylamine (0.59 mL) wasadded followed by bromoacetic anhydride (1.043 g) in methylene chloride(1 mL). After 30 mintues, the solvents were removed in vacuo and theresidue obtained triturated with ether and filtered. The solid obtainedwas washed with water and dried to afford the title compound (0.7 g,47%). ¹ H NMR (CD₃ OD, 300 MHz) δ0.80 (m, 12H), 2.83 (m, 4H), 3.42 (s,2H), 3.83 (d of d, 2H), 4.05 (m, 2H), 4.60 (m, 2H), 7.07-7.27 (m, 10H),7.52 (d, 2H). MS (FAB) m/e 741 (M+H)⁺.

Example 2522,5-Di-{N-[(1-Methylimidazol-2-yl)-thiomethylcarbonyl]-(L)-Valyl}amino-3,4-dihydroxy-1,6-diphenylhexane

To a solution of the resultant compound of Example 251 (100 mg, 0.135mmol) dissolved in dimethylformamide containing triethylamine (40 μL)was added 2-mercapto-1-methyl imidazole (31 mg). The reaction mixturewas stirred at room temperature for 30 minutes. The solvent was removedunder reduced pressure and chased with 10% methanol in methylenechloride. The residue obtained was chromatographed on silica gel elutngwith 10% methanol in methylene chloride to afford the title product (62mg, 57%). ¹ H NMR (CDCl₃, 300 MHz) δ0.83 (m, 12H), 2.17 (m, 2H), 2.85(m, 4H), 3.40-3.80 (m, 10H), 4.20 (m, 2H), 4.47-4.85 (m, 2H), 6.82-7.37(m, 14H), 8.69 (bd, 2H). MS (FAB) m/e 807 (M+H)⁺.

Example 2532,5=Di-{N-[(Imidazol-2-yl)-thiomethylcarbonyl]-(L)-Valyl}amino-3,4-dihydroxy-1,6-diphenylhexane

The resultant compound of Example 251 (150 mg, 0.2 mmol) was reactedwith 2-mercaptoimidazole (40.6 mg) by the procedure described in Example252 and similarly purified to afford the title compound (74 mg, 47%). ¹H NMR (DMSO-d₆, 300 MHz) δ0.63 (m, 12H), 1.84 (m, 2H), 2.25-2.80 (m,4H), 3.05-3.82 (m, 12H), 4.44 (m, 2H), 7.14 (m, 14H), 7.48 (bd, 2H),8.07 (bd, 2H). MS (FAB) m/e 779 (M+H)⁺.

Example 2542,5-Di-{N-[N-Methyl-N-(2-pyridylmethyl)aminocarbonyl]-(L)-Valyl}amino-3,4-dihydroxy-1,6-diphenylhexane

The resultant compound of Example 4A (199 mg, 0.66 mmol) and theresultant compound of Example 3F (766 mg) were dissolved in anhydrousdimethylformamide (3 mL) and stirred overnight at room temperature. Thereaction mixture was diluted with ethyl acetate and washed withsaturated sodium bicarbonate (3x) and water. The organic phase was driedover magnesium sulfate and concentrated under reduced pressure. Theresidue obtained was chromatographed on silica gel eluting with 5%methanol in methylene chloride to afford the title compound (303 mg,58%). ¹ H NMR (CDCl₃, 300 MHz) δ0.68 (d, 6H), 0.86 (d, 6H), 2.13 (m,2H), 2.87 (m, 4H), 3.00 (s, 6H), 3.57 (bs, 2H), 4.00 (d of d, 2H), 4.25(m, 4H), 4.48 (s, 4H), 6.40 (m, 4H), 7.07-7.30 (m, 14H), 7.74 (d of t,2H), 8.54 (d, 2H). MS (FAB) m/e 795 (M+H)⁺, 817 (M+Na)⁺.

Example 255 2,5-Di-{N-[N-Methyl-N-(2-pyridylmethyl)aminocarbonyl]-(L)-Valyl}amino-3,4-dihydroxy-1,6-diphenylhexane 3-O, 4-O -Carbonate

To the resultant compound of Example 254 (300 mg, 0.31 mmol) dissolvedin tetrahydrofuran (15 mL) at room temperature and then cooled to 0° C.was added N-methyl morpholine (0.125 mL) followed by triphosgene (112mg). The cooling bath was removed and the reaction mixture was stirredfor 3 hours at room temperature and then concentrated under reducedpressure. The residue obtained was washed with water and extracted withmethylene chloride. The organic layer was dried over magnesium sulfateand concentrated under reduced pressure. The residue obtained waschromatographed on silica gel eluting with 5% methanol in methylenechloride to afford the title compound (247 mg, 80%). m.p. 118°-119° C. ¹H NMR (CDCl₃, 300 MHz) δ0.69 (d, 6H), 0.79 (d, 6H), 2.04 (m, 2H),2.74-3.04 (m, 4H), 3.00 (s, 6H), 3.95 (t, 2H), 4.40 (s, 4H), 4.58 (m,4H), 6.56 (bd, 4H), 7.10-7.32 (m, 14H), 7.75 (d of t, 2H), 8.51 (m, 2H).Anal calcd for C₄₅ H₅₆ N₈ O₇ : C, 65.83; H, 6.88; N, 13.65. Found: C,65.72; H, 7.44; N, 12.36. MS (FAB) m/e 821 (M+H)⁺.

Example 2562,5-Di-{N-[(2-Pyridylmethyl)oxycarbonyl]-(L)-Isoleucyl}amino-34-dihydroxy-1,6-diphenyl hexane

The resultant compound of Example 4A (150 mg, 0.5 mmol) and theresultant compound of Example 25C (580 mg) were stirred indimethylformamde (3 mL) at room temperature overnight. The reactionmixture was diluted with ethyl acetate and washed with sodiumbicarbonate (3x). The organic layer was dried over magnesium sulfate andconcentrated under reduced pressure to afford the title compound (278mg, 70%). m.p. 220°-221° C. ¹ H NMR (DMSO-d₆, 300 MHz) δ0.58 (d, 6H),0.73 (t, 6H), 0.97 (m, 2H), 1.22 (m, 2H), 1.59 (m, 2H), 2.54-2.73 (m,4H), 3.82 (d of d, 2H), 4.52 (m, 2H), 4.82 (bs, 2H), 5.10 (d of d, 4H),7.03-7.42 (m, 20H), 7.84 (d of t, 2H), 8.55 (bd, 2H). MS (FAB) m/e 797(M+H)⁺, 819 (M+Na)⁺.

Example 2572,5-Di-{N-[(2-pyridylmethyl)oxycarbonyl]-(L)-Valyl}amino-3,4-dihydroxy-1,6-diphenylhexane 3-O,4-O-Carbonate

The resultant compound of Example 260 (300 mg, 0.39 mmol) was reactedwith triphosgene (116 mg) by the procedure described in Example 255.Purification as described in Example 255 gave the title product (268 mg,86%). m.p. 118°-120° C. ¹ H NMR (CDCl₃, 300 MHz) δ0.74 (d, 6H), 0.84 (d,6H), 1.98 (m, 2H), 2.67-2.98 (m 4H), 3.98 (m, 2H), 4.53 (m, 4H), 5.23(m, 4H), 6.80 (bd, 4H), 7.10-7.38 (m, 14H), 7.70 (d of t, 2H), 8.60 (d,2H). Anal calcd for C₄₃ H₅₀ N₆ O₉.0.5 H₂ O: C, 64.24; H, 6.39; N, 10.45.Found: C, 63.91; H, 6.33; N, 10.38. MS (FAB) m/e 795 (M+H)⁺.

Example 2582,5,Di-{N-[(2-pyridylmethyl)oxycarbonyl]-(L)-Valyl}amino-3,4-dihydroxy-1,6-diphenylhexane 3-O; 4-O-Thiocarbonate

To the resultant compound of Example 260 (300 mg, 0.26 mmol) dissolvedin toluene (5 mL) was added thiocarbonyldiimidazole (140 mg). Thereaction mixture was warmed at reflux for 3 hours and diluted withmethylene chloride and washed with 10% citric acid (2x). The organicphase was dried over magnesium sulfate and concentrated under reducedpressure to afford the title compound (177 mg, 56%). m.p. 115°-117° C. ¹H NMR (CDCl₃, 300 MHz) δ0.66 (d, 6H), 0.80 (d, 6H), 2.00 (m, 2H), 2.94(m, 4H), 3.84 (d of d, 2H), 4.60 (m, 2H), 5.08 (bd, 2H), 5.20 (s, 4H),6.23 (bd, 4H), 7.00-7.40 (m, 14H), 7.72 (d of t, 2H), 8.61 (bd, 2H).Anal calcd for C₄₃ H₅₀ N₆ O₈ S.0.5 H₂ O: C, 62.98; H, 6.27; N, 10.25.Found: C, 62.69; H, 6.13; N, 10.15. MS (FAB) m/e 811 (M+H)⁺.

Example 2592,5-Di-{N-[N-Methyl-N-(2-pyridylmethyl)aminocarbonyl]-(L)-Isoleucyl}amino-3,4-dihydroxy-1,6-diphenylhexane

The resultant compound of Example 4A (150 mg) and the resultant compoundof Example 16C (630 mg) were stirred in anhydrous dimethylformamide (3mL) overnight at room temperature. The reaction mixture was diluted withethyl acetate and washed with saturated sodium bicarbonate solution (2x)and water. The organic layer was dried over magnesium sulfate andconcentrated under reduced pressure. The residue obtained waschromatographed on silica gel eluting with 4% methanol in methylenechloride to afford the title compound (250 mg, 81%). m.p. 160°-161° C. ¹H NMR (CDCl₃, 300 MHz) δ0.78 (m, 12H), 0.84-1.13 (m, 4H), 1.87 (m, 2H),2.87 (m, 4H), 2.97 (s, 6H), 3.58 (s, 2H), 4.02 (d of d, 2H), 4.27 (m,4H), 4.45 (s, 4H), 6.35 (bs, 2H), 6.45 (bd, 2H), 7.07-7.30 (m, 14H),7.74 (d of t, 2H), 8.03 (m, 2H). Anal calcd for C₄₆ H₆₂ N₈ O₆ : C,67.13; H, 7.59; N, 13.62. Found: C, 67.06; H, 7.54; N, 13.55. MS(DCI/NH₃) m/e 823 (M+H)⁺.

Example 260 2,5-Di-{N-[(2-Pyridylmethyl)oxycarbonyl]-(L)-valinyl}amino-3,4-dihydroxy-1,6-diphenyl hexane

The resultant compound of Example 4A (2.5 g, 8.3 mmol) was reacted withthe resultant compound of Example 2D (9.00 g) by the procedure describedin Example 254. Crystallization from methylene chloride and ethylacetate afforded the title compound (2.88 g, 45%). m.p. 221° C. ¹ H NMR(DMSO-d₆, 300 MHz) δ0.64 (d, 6H), 0.70 (d, 6H), 1.82 (m, 2H), 2.56-2.83(m, 4H), 3.78 (m, 2H), 4.50 (m, 2H), 4.85 (bs, 2H), 5.10 (s, 4H),7.05-7.42 (m, 20H), 7.84 (d of t, 2H), 8.54 (bd, 2H). Anal calcd for C₄₂H₅₂ N₆ O₈ : C, 65.61; H, 6.82; N, 10.93. Found: C, 65.60; H, 6.85; N,10.94. MS (FAB) m/e 769 (M+H)⁺.

Example 261 (2S, 3S,5S)-2,5-Di-(Boc-amino)-1,6-diphenyl-3-hydroxy-hexane

To a solution of the resultant compound of Example 1E (1.00 g, 4.1 mmol)dissolved in methylene chloride (40 mL) was added di-t-butyldicarbonate(1.98 g, 2.2 equiv). The reaction mixture was stirred at roomtemperature for 1 hour and then concentrated in vacuo at 40° C. Theresidue obtained was chromatographed on silica gel eluting with 1:3going to 1:2 ethyl acetate/hexane to afford the title compound (1.315 g,72%). ¹ H NMR (CDCl₃, 300 MHz) δ1.39 (s, 18H), 1.62 (m, 2H), 2.74 (d,2H), 2.85 (t, 2H), 3.64 (m, 2H), 3.86 (d of d, 1H), 4.55 (bs, 1H), 4.80(bd, 1H), 7.07-7.32 (m, 10H). Anal calcd for C₂₈ H₄₀ N₂ O₅ : C, 69.39;H, 8.32; N, 5.78. Found: C, 69.21; H, 8.38; N, 5.73. MS (DCI/NH₃) m/e485 (M+H)⁺, 502 (M+H+NH₃)⁺.

Example 262 (2S, 3S,5S)-1,6-Diphenyl-2,5di-(phenyloxycarbonyl)-3-hydroxy-hexane

To a solution of the resultant compound of Example 1E (100 mg, 0.35mmol) and anhydrous triethylamine (0.12 mL, 2.5 equiv) dissolved inanhydrous methylene chloride (4 mL) and cooled under nitrogen to -40° C.was added phenyl chloroformate (0.09 mL, 2 equiv). After stirring at-40° C. for 1 hour, the reaction mixture was diluted with methylenechloride (50 mL) and washed with saturated sodium bicarbonate (20 mL)and saturated sodium chloride (20 mL). The organic phase was dried overmagnesium sulfate and concentrated under reduced pressure. The residueobtained was chromatographed on silica gel eluting with 1:4 going to 1:2going to 1:1 ethyl acetate/hexane to afford the title compound (64 mg,35%). ¹ H NMR (CDCl₃, 300 MHz) δ1.80 (m, 2H), 2.86 (d, 2H), 2.94 (d ofd, 2H), 3.02 (bd, 1H), 3.76 (bs, 1H), 3.86 (d of d, 1H), 4.03 (d of d,1H), 5.13 (bd, 1H), 5.35 (bd, 1H), 7.00-7.40 (m, 20H). MS (DCI/NH₃) m/e525 (M+H)⁺, 542 (M+H+NH₃)⁺.

Example 263 (2S, 3S, 5S)-2,5-Di-(isopropyloxycarbonylamino)-1,6-diphenyl-3-hydroxy-hexane

The resultant compound of Example 1E (100 mg, 0.35 mmol) was reactedwith 1M isopropyl chloroformate in toluene (0.70 mL, 2.0 equiv) by theprocedure described in Example 262. Column chromatography on silica geleluting with 1:2 going to 1 ethyl acetate/hexane afforded the titlecompound (92 mg, 57%). ¹ H NMR (CDCl₃, 300 MHz) δ1.17 (m, 12H), 1.63 (m,2H), 2.75 (d, 2H), 2.86 (m, 2H), 3.31 (bs, 1H), 3.69 (m, 2H), 3.90 (m,1H), 4.63 (m, 1H), 4.89 (m, 3H), 7.04-7.42 (m, 10H). Anal calcd for C₂₆H₃₆ N₂ O₅ : C, 68.40; H, 7.95; N, 6.14. Found: C, 68.10; H, 7.99; N,6.14. MS (DCI/NH₃) m/e 457 (M+H)⁺, 474 (M+H+NH₃)⁺.

Example 264 (2S, 3S,5S)-2,5-Di-(3,3-dimethylacryloylamino)-1,6-diphenyl-3-hydroxy-hexane

The resultant compound of Example 1E (150 mg, 0.53 mmol) was reactedwith 3,3-dimethylacryloyl chloride (0.12 mL, 2.0 equiv) by the proceduredescribed in Example 262 except that pyridine (0.26 mL, 6 equiv) wasused instead of triethylamine. Column chromatography on silica geleluting with 1:2 going to 1:1 ethyl acetate/hexane afforded the titlecompound (182 mg, 77%). ¹ H NMR (CDCl₃, 300 MHz) δ1.65 (m, 3H), 1.82 (m,6H), 2.10 (m, 6H), 2.87 (m, 2H), 2.90 (m, 2H), 3.62 (m, 1H), 3.96 (m,1H), 4.10 (m, 1H), 4.62 (bs, 1H), 5.43 (m, 1H), 5.50 (m, 1H), 5.53 (bd,1H), 5.72 (bd, 1H), 7.05-7.30 (m, 10H). Anal calcd for C₂₈ H₃₆ N₂ O₃ :C, 74.97; H, 8.09; N, 6.24. Found: C, 74.25; H, 8.43; N, 6.12. MS(DCI/NH₃) m/e 449 (M+H)⁺, 466 (M+H+NH₃)⁺.

Example 265 (2S, 3S,5S)-2,5-Di-(isovalerylamino)-1,6-diphenyl-3-hydroxy-hexane

The resultant compound of Example 1E (150 mg, 0.53 mmol) was reactedwith isovaleryl chloride (0.13 mL, 2.0 equiv) by the pyridine proceduredescribed in Example 264. Column chromatography eluting with 1: 2 goingto 1: 1 going to 2: 1 ethyl acetate/hexane afforded the title compound(38 mg, 16%). ¹ H NMR (CDCl₃, 300 MHz) δ0.84 (m, 12H), 1.65 (m, 3H),1.97 (m, 6H), 2.78 (m, 2H), 2.89 (d, 2H), 3.63 (bs, 1H), 3.99 (m, 1H),4.10 (m, 1H), 4.52 (bs, 1H), 5.60 (d, 1H), 5.80 (d, 1H) 7.07-7.30 (m,10H) MS (DCI/NH₃) m/e 453 (M+H)⁺, 470 (M+H+NH₃)⁺.

Example 266 (2S,3S,5S)-2,5-Di-(isobutyloxycarbonylamino)-1,6-diphenyl-3-hydroxy-hexane

The resultant compound of Example 1E (100 mg, 0.35 mmol) was reactedwith isobutylchloroformate (0.09 mL, 2.0 equiv) by the proceduredescribed in Example 262. Column chromatography on silica gel elutingwith 1:2 ethyl acetate/hexane afforded the title compound (114 mg, 69%).¹ H NMR (CDCl₃, 300 MHz) δ0.89 (m, 12H), 1.65 (m, 2H), 1.86 (m, 2H),2.77 (bd, 2H), 2.87 (m, 2H), 3.30 (bs, 1H), 3.60-3.97 (m, 7H), 4.70 (m,1H), 4.97 (bd, 1H), 7.07-7.32 (m, 10H). Anal calcd for C₂₈ H₄₀ N₂ O₅ :C, 69.39; H, 8.32; N, 5.78. Found: C, 69.20; H, 8.32; N, 5.75. MS(DCI/NH₃) m/e 485 (M+H)⁺, 502 (M+H+NH₃)⁺.

Example 267 (2S,3R, 5S)-1,6-Diphenyl-3-hydroxy-2,5-di-(Boc-amino)-hexaneA. 1.6-Diphenyl-3-oxo-2.5-di-(Boc-amino)-hexane

To a solution of oxalyl choride (0.09 mL, 1.03 mmol) dissolved inanhydrous methylene chloride (3 mL) and cooled to -78° C. was addeddimethyl sulfoxide-(0.147 mL, 2.07 mmol) dropwise. The reaction mixturewas stirred at -78° C. for 10 minutes and then a solution of theresultant compound of Example 261 (250 mg, 0.52 mmol) dissolved inanhydrous methylene chloride (5 mL) was added dropwise. After stirringat -78° C. for 1 hour, anhydrous triethylamine (0.57 mL, 4.12 mmol) wasadded, the cooling bath was removed, and the reaction mixture wasstirred for 15 minutes. The reaction mixture was diluted with methylenechloride (50 mL) and washed with saturated sodium bicarbonate (20 mL)and saturated sodium chloride (20 mL), dried over magnesium sulfate, andconcentrated in vacuo. The residue obtained was chromatographed onsilica gel eluting with 1:6 going to 1:4 ethyl acetate/hexane to affordthe title compound (235 mg, 94%). MS (DCI/NH₃) m/e 483 (M+H)⁺, 500(M+H+NH₃)⁺.

B. (2S,3S, 4R)-1.6-Diphenyl-3-hydroxy-2,5-di-(Boc-amino)-hexane

To the resultant compound of Example 267A (20 mg, 0.04 mmol) dissolvedin methanol (0.4 mL) and methylene chloride (0.3 mL) and cooled to -78°C. was added sodium borohydride (1.6 mg, 1.0 equiv). The reactionmixture was allowed to slowly warm to -20° C. and maintained at thattemperature for 18 hours. The reaction mixture was diluted withmethylene chloride (10 mL) and washed with saturated sodium chloridesolution (3 mL), dried over magnesium sulfate, and concentrated invacuo. The residue obtained was chromatographed on silica gel elutingwith 1:4 going to 1:2 ethyl acetate/hexane to afford the title compound(14.7 mg, 73%). ¹ H NMR (CDCl₃, 300 MHz) δ1.35 (s, 9H), 1.40 (s, 9H),1.42-1.73 (m, 3H), 2.80 (m, 2H), 2.87 (bd, 2H), 3.56 (bs, 1H), 3.84 (bs,1H), 4.15 (m, 1H), 4.46 (m, 1H), 4.59 (m, 1H), 7.12-7.32 (m, 10H). MS(DCI/NH₃) m/e 485 (M+H)⁺.

Example 268 1,5-Dichloro-2,3,4-triformyl arabitol

To a solution of anhydrous dimethylformamide (146 mL, 1.9 mol) inanhydrous methylene chloride (1450 mL) at 0° C. was added dropwiseoxalyl chloride (126 mL, 1.5 mol). The reaction mixture was stirred at0° C. under nitrogen for 1 hour and then a solution of arabitol (22 g,0.14 mmol) dissolved in dimethylformamide (350 mL) was added at such arate that the temperature remained below 5° C. After the addition wascomplete, the bath was removed and the reaction mixture was stirredat-room temperature under nitrogen for 1 hour and then at reflux for 7hours. The reaction mixture was diluted with ethyl acetate (2 L) andwashed with cold water (2 L). The aqueous layer was back-extracted withethyl acetate (1 L). The combined organic extracts were washed withsaturated sodium chloride (1 L), dried over magnesium sulfate andconcentrated under reduced pressure to afford crude material (58.2 g).Chromatography on silica gel eluting with a gradient of 2:8 to 8:2methylene chloride/hexane gave the title compound (21.7 g, 55%). ¹ H NMR(CDCl₃, 300 MHz) δ3.61 (d, 2H), 3.66 (d of d, 2H), 3.81 (d of d, 1H),5.35 (m, 1H), 5.50 (m, 1H), 5.71 (m, 1H), 8.08 (s, 1H), 8.10 (s, 1H),8.19 (s, 1H). Anal calcd for C₈ H₁₀ C₁₂ O₆ : C, 35.19; H, 3.69. Found:C, 35.30; H, 3.75. MS (DCI/NH₃) m/e 290 (M+H+NH₃)⁺. High Resolution MassSpec calcd for C₈ H₁₀ Cl₂ O₆ : 272.9933. Found: 272.9930. IR (CDCl₃)1150, 1720 cm⁻¹. [α]_(D) =+31.1° (c=1.12, CHCl₃, 22° C.).

Example 269 1,2:4,5-Bis-epoxy-3-hydroxy-pentane

To the resultant compound of Example 268 (1.00 g, 3.7 mmol) dissolved inanhydrous tetrahydrofuran (20 mL) and cooled to 0° C. under nitrogen wasadded sodium methoxide (1.00 g, 6 equiv). The reaction mixture wasstirred at 0° C. under nitrogen for 30 minutes and then diluted withether (40 mL) and filtered through Celite. The filtrate was concentratedin vacuo to afford crude material (278 mg). Chromatography on silica geleluting with 1:1 ethyl acetate/hexane afforded the title compound (102mg, 24%). ¹ H NMR (CDCl₃, 300 MHz) δ2.04 (d, 1H), 2.79-2.89 (m, 4H),3.11-3.20 (m, 2H), 3.60 (d of d, 1H). MS (DCI/NH₃) m/e 134 (M+H+NH₃)⁺.IR (CDCl₃) 3540 3060 3000 2925 cm⁻¹. [α]_(D) =-4.3° (c=1.07, CHCl₃, 22°C.).

Example 270 1,2:4,5-Bis-epoxy-3-methanesulfonyloxy-pentane

To the resultant compound of Example 269 (4.2456 g, 36.6 mmol) dissolvedin anhydrous tetrahydrofuran (200 mL) and cooled to -20° C. undernitrogen was added sodium hydride (878 mg, 1.0 equiv). The reactionmixture was stirred at 0° C. for 30 minutes and then cooled to -20° C.and treated with anhydrous triethylamine (9.2 mL, 1.9 equiv) andmethanesulfonyl chloride (4.3 mL, 1.5 equiv). After stirring at -20° C.under nitrogen for 30 minutes, the reaction was diluted with chloroform(400 mL) and washed with pH 6 phosphate buffer (80 mL). The aqueous washwas back-extracted with chloroform (100 mL). The combined organicextracts were dried over magnesium sulfate and concentrated in vacuo togive crude material (9.8 g). Chromatography on silica gel eluting with8:2 methylene chloride/hexane going to 9/1 methylene chloride/ethylacetate gave the title compound (6.23 g, 88%). ¹ H NMR (CDCl₃, 300 MHz)δ2.80-2.85 (m, 2H), 2.92 (d of d, 1H), 2.98 (d of d, 1H), 3.14 (s, 3H)3.24-3.33 (m, 2H), 4.13 (d of d, 1H). Anal calcd for C₆ H₁₀ O₅ S: C,37.11; H, 5.19. Found: C, 36.52; H, 5.12. MS (DCI/NH₃) m/e 212(M+H+NH₃)⁺. IR (CDCl₃) 1365, 1175, 955 cm⁻¹. [α]_(D) =+3.9° (c=1.44,CHCl₃, 22° C.).

Example 271 1,5-Dichloro-2,3,4-trihydroxy pentane

The resultant compound of Example 268 (250 mg, 0.92 mmol) was dissolvedin methanol (5 mL), stirred at 50° C. for 1 hour, and then concentratedin vacuo to give crude material (192 mg). Chromatography on silica geleluting with 1:1 ethyl acetate/hexane afforded the title compound (172mg, 99%). ¹ H NMR (D20, 300 MHz) δ3.67-3.71 (m, 2H), 3.76-3.79 (m, 1H),3.86-3.89 (m, 2H), 3.96-4.02 (m, 1H), 4.06-4.11 (m, 1H). ¹³ C NMR (D₂ O,300 MHz) PPM 48.278, 50.574, 72.434, 72.741, 72.951. Anal calcd for C₅H₁₀ Cl₂ O₃ : C, 31.77; H, 5.33. Found: C, 31.67; H, 5.29. MS (DCI/NH₃)m/e 206 (M+H+NH₃)⁺. [α]_(D) =-3.2° (c=1.21, H₂ O, 22° C.).

Example 272 (2S, 3S,5S)-1,6-Diphenyl-2,5-di[N-(furan-2-ylmethyloxycarbonyl)amino]-3-hydroxyhexane A. (Furan-2-yl) (4-nitrophenyl)carbonate

To a solution of 2-furanmethanol (413 mg, 0.261 mmol) andN-methylmorpholine (468 μL, 4.261 mmol) dissolved in methylene chloride(3 mL) and cooled in an ice bath was added a solution of4-nitrophenylchloroformate (859 mg, 4.261 mmol) dissolved in methylenechloride (3 mL). The mixture was stirred at 0° C. for 3.5 hours and thenworked up to give a residue which was chromatographed on silica geleluting with 10% ethyl acetate in hexane followed by 10% ethyl acetatein methylene chloride to afford the title compound (113 mg) aftercyrstallization from ethyl acetate and hexane.

B. (2S, 3S,5S)-1,6-Diphenyl-2,5-di[N-(furan-2-ylmethyloxycarbonyl)amino]-3-hydroxy hexane

To the compound resulting from Example 1E (75 mg, 0.264 mmol) dissolvedin dimethylformamide (0.6 mL) was added the compound resulting fromExample 272A (208 mg, 0.79 mmol). The mixture was stirred at roomtemperature overnight and then the solvent removed under reducedpressure. The crude product was chromatograhed on silica gel elutingwith 5-10% ethyl acetate in methylene chloride to afford the titlecompound. ¹ H NMR (DMSO-d₆, 300 MHz) δ1.46 (m, 2H), 2.53-2.79 (m, 5H),3.57 (m, 1H), 3.89 (m, 3H), 4.64 (d, 1H), 4.79-4.95 (m, 5H), 6.41 (m,4H), 6.89 (d, 1H), 7.08-7.29 (m, 13H), 7.63 (m, 2H). Anal calcd for C₃₀H₃₂ N₂ O₇ : C, 67.67; H, 6.01; N, 5.26. Found: C, 67.25; H, 5.94; N,5.22. MS (DCI/NH₃) m/e 533 (M+H)⁺, 550 (M+H+NH₃)⁺.

Example 273 (2S, 3S, 5S)-1,6-Diphenyl-2,5-di[N-(furan-3-ylmethyloxycarbonyl)amino]-3-hydroxy hexane

(Furan-3-yl) (4-nitrophenyl)carbonate was prepared in analogy to Example272A starting from 3-furanmethanol instead of 2-furanmethanol. Thecompound resulting from Example 1E (70 mg, 0.249 mmol) was reacted withthe above carbonate (144 mg, 0.548 mmol) by the procedure described inExample 272B to afford crude material. Column chromatography on silicagel eluting with a gradient (5%,10%,50%) of ethyl acetate in methylenechloride afforded the title compound. ¹ H NMR (DMSO-d₆, 300 MHz) δ1.48(m, 2H), 2.52-2.78 (m, 5H), 3.56 (m, 1H), 3.88 (m, 2H), 4.64 (d, 1H),4.78 (d, 4H), 6.37 (s, 2H), 6.78 (d, 1H), 7.03 (d, 1H), 7.10-7.28 (m,10H), 7.60 (m, 3H). Anal calcd for C₃₀ H₃₂ N₂ O₇ : C, 67.67; H, 6.01; N,5.26. Found: C, 67.31; H, 5.99, N, 5.21. MS (DCI/NH₃) m/e 533 (M+H)⁺,550 (M+H+NH₃)⁺.

Example 274(2S,3S,5S)-1,6-Diphenyl-2,5-di[N-(5-bromopyridin-3-ylmethyloxycarbonyl)amino]-3-hydroxyhexane A. (5-Bromo-pyridin-3-ylmethyl) (4-nitrophenyl)carbonate

5-Bromo-nicotinic acid (5,00 g, 24.7 mmol) was dissolved in methanol (50mL) and saturated with hydrochloric acid gas. The reaction mixture wasallowed to stand for 2.5 days and then filtered. The filtrate wasconcentrated under reduced pressure and methylene chloride was added.The solution was washed with saturated sodium bicarbonate solution. Theaqueous wash was back-extracted with methylene chloride (2x). Thecombined organic extracts were dried over magnesium sulfate andconcentrated in vacuo to afford 5-bromo-nicotinic acid methyl ester(4.72 g).

To the above methyl ester (4.536 g, 21 mmol) dissolved intetrahydrofuran (15 mL) and cooled in a dry ice/acetone bath was added1M lithium aluminum hydride (21 mL, 21 mmol) diluted withtetrahydrofuran (10 mL). The reaction mixture was stirred for 40 minutesand then water (0.80 mL) followed by 15% sodium hydroxide (0.80 mL) andwater (2.4 mL) were added. The mixture was stirred for 1 hour andfiltered. The filtrate was dried over magnesium sulfate and concentratedunder reduced pressure. The crude product was chromatographed on silicagel eluting with 2% methanol in methylene chloride to afford5-bromo-3-pyridinemethanol (2.472 g).

The above compound (817 mg, 4.346 mmol) was reacted with4-nitrophenylchloroformate (1.051 g, 5.21 mmol) by the proceduredescribed in Example 272A to give the title compound (847 mg, 55%).

B. (2S; 3S;5S)-1,6-Diphenyl-2,5-di[N-(5-bromopyridin-3-ylmethyloxycarbonyl)amino]-3-hydroxyhexane

The compound resulting from Example 1E (65 mg, 0.229 mmol) was reactedwith the compound resulting from Example 274A (242 mg, 0.687 mmol) bythe procedure described in Example 272B to give the title compound (114mg, 70%). ¹ H NMR (DMSO-d₆, 300 MHz) δ1.50 (m, 2H), 2.53-2.74 (m, 5H),3.56 (m, 1H), 3.76 (m, 2H), 4.72 (d, 1H), 4.98 (d, 4H), 6.99-7.25 (m,12H), 7.92 (m, 2H), 8.49 (m, 2H), 8.64 (dd, 2H). Anal calcd for C₃₂ H₃₂Br₂ N₄ O₅ : C, 53.93; H, 4.49; N, 7.86. Found: C, 54.46; H, 4.63; N,7.93. MS (DCI/NH₃) m/e 711 (M+H)⁺.

Example 275(2S,3S,5S)-1,6-Diphenyl-2,5-di[N-(5-methylpyridin-3-ylmethyloxycarbonyl)amino]-3-hydroxyhexane

5-Methylpyridine-3-methanol was prepared in analogy to the proceduredescribed in Example 274A. It was reacted with4-nitrophenylchloroformate by the procedure described in Example 272A togive (5-methylpyridin-3-yl) (4-nitrophenyl) carbonate (474 mg).

The compound resulting from Example 1E (36.1 mg, 0.127 mmol) was reactedwith the above carbonate (110 mg, 0.38 mmol) by the procedure describedin Example 272B to give crude material. Column chromatography on silicagel eluting with a gradient (2%,5%) methanol in methylene chlorideafforded the title compound (64 mg). ¹ H NMR (DMSO-d₆, 300 MHz) δ1.48(m, 2H), 2.25 (d, 6H), 2.52-2.73 (m, 5H), 3.55 (m, 1H), 3.88 (m, 2H),4.68 (d, 1H), 4.93 (d, 4H), 6.92 (d, 1H), 7.08-7.26 (m, 12H), 7.46 (s,2H), 8.32 (m, 3H). Anal calcd for C₃₄ H₃₈ N₄ O₅ : C, 70.10; H, 6.53; N,9.62. Found: C, 70.29; H, 6.62; N, 9.60. MS (DCI/NH₃) m/e 583 (M+H)⁺.

Example 276 (2S;3S,5S)-1,6-Diphenyl-2,5-di[N-(N-Boc-6-amino-pyridin-3-ylmethyloxycarbonyl)amino]-3-hydroxyhexane

6-Amino-nicotinic acid (5.00 g, 36.2 mmol) was esterified by theprocedure described in Example 274A to give the methyl ester. To themethyl ester (2.013 g, 9.32 mmol) dissolved in acetonitrile (80 mL) wasadded di-t-butyldicarbonate (2.235 g, 10.25 mmol) followed bydimethylaminopyridine (122 mg, 1.0 mmol). The reaction mixture wasstirred at room temperature for 4 hours and then additionaldi-t-butyl-dicarbonate (450 mg) was added. The reaction mixture wasstirred an additional hour at room temperature and then stored in therefrigerator overnight. The solvent was removed under reduced pressureand the crude material chromatographed on silica gel eluting with agradient (5%,10%) of ethyl acetate in methylene chloride to afford theN-Boc-6-amino-nicotinic acid methyl ester (1.85 g, 79%).

The methyl ester (1.85 g, 7.34 mmol) was reduced with lithium aluminumhydride by the procedure described in Example 274A to give, afterchromatography on silica gel eluting with a gradient (2%,5%) of methanolin methylene chloride, N-Boc-6-amino-pyridine-3-methanol (1.064 g). Thiscompound (311 mg, 1.388 mmol) was reacted with4-nitrophenylchloroformate (308 mg, 1.53 mmol) by the proceduredescribed in Example 272A to give (N-Boc-6-amino-pyridin-3-ylmethyl)(4-nitrophenyl)carbonate (388 mg).

The compound resulting from Example 1E (87 mg, 0.301 mmol) was reactedwith the above carbonate (340 mg, 0.904 mmol) by the procedure describedin Example 272B to give crude material. Chromatography on silica geleluting with a gradient (2%,5%) of methanol in methylene chlorideafforded the title compound (133 mg). ¹ H NMR (DMSO-d₆, 300 MHz) δ1.47(s, 20H), 2.53-2.75 (m, 5H), 3.55 (m, 1H), 3.87 (m, 2H), 4.65 (d, 1H),4.89 (d, 4H), 6.87 (d, 1H), 7.07-7.27 (m, 11H), 7.59 (dd, 2H), 7.75 (dd,2H), 8.18 (m, 2H), 9.80 (d, 2H). Anal calcd for C₄₂ H₅₂ N₆ O₉.0.33H₂ O:C, 63.80; H, 6.71; N, 10.63. Found: C, 63.94; H, 6.67; N, 10.57.MS (FAB)M/E 785 (M+1).

Example 277 (2S,3S,5S)-1,6-Diphenyl-2-[N-(furan-3-ylmethyloxycarbonyl)amino]-5-[N-(pyridin-3-ylmethyloxycarbonyl)amino]-3-hydroxyhexane

3-Pyridinemethanol was reacted with 4-nitrophenylchloroformate by theprocedure described in Example 272A to give the (3-pyridylmethyl)(4-nitrophenyl)carbonate. This compound was reacted with the compoundresulting from Example 1E by the procedure described in Example 272B togive a mixture of 2- and 5- substituted compounds which were separableby column chromatography. The (2S, 3R,5S)-1,6-diphenyl-5-[N-(pyridin-3-ylmethyloxycarbonyl)amino]-3-hydroxyhexane compound (55 mg, 0.131 mmol) was reacted with (furan-3-yl)(4-nitrophenyl)carbonate, prepared as described in Example 273, by theprocedure described in Example 272B to give, after chromatography onsilica gel eluting with a gradient (2%,5%) of methanol in methylenechloride, the title compound (63.1 mg). ¹ H NMR (DMSO-d₆, 300 MHz) δ1.50(m, 2H), 2.54-2.75 (m, 5H), 3.56 (m, 1H), 3.88 (m, 2H), 4.66 (d, 1H),4.68-4.92 (m, 1H), 4.79 (s, 2H), 4.97 (s, 2H), 6.37 (m, 1H), 6.79 (d,1H), 6.90-7.38 (m, 12H), 7.25 (dd, 1H), 7.6 (m, 3H), 8.50 (m, 2H). Analcalcd for C₃₁ H₃₃ N₃ O₆.0.33 H₂ O: C, 67.78; H, 6.19; N, 7.65. Found: C,67.97; H, 6.15; N, 7.69. MS (DCI/NH₃) m/e 544 (M+H)⁺.

Example 278(2S,3S,5S)-1,6-Diphenyl-5-[N-(furan-3-ylmethyloxycarbonyl)amino]-2-[N-(pyridin-3-ylmethyloxycarbonyl)amino]-3-hydroxyhexane

The other regio-isomer described in Example 277, (2S, 3R,5S)-1,6-diphenyl-2-[N-(pyridin-3-ylmethyloxycarbonyl)amino]-3-hydroxyhexane, (31.7 mg, 0.0756 mmol) was reacted with (furan-3-yl)(4-nitrophenyl)carbonate (24 mg, 0.091 mmol), prepared as described inExample 273, by the procedure described in Example 272B to give, aftercolumn chromatography on silica gel eluting with a gradient (2%,5%)methanol in methylene chloride, the title compound (22.7 mg). ¹ H NMR(DMSO-d₆, 300 MHz) δ1.48 (m, 2H), 2.53-2.76 (m, 5H), 3.57 (m, 1H), 3.87(m, 2H), 4.68 (d, 1H), 4.77 (s, 2H), 4.99 (s, 2H), 6.37 (s, 1H), 6.95(d, 1H), 7.03 (d, 1H), 7.08-7.27 (m, 10H), 7.33 (dd, 1H), 7.60 (m, 3H),8.50 (m, 2H). MS (DCI/NH₃) m/e 544 (M+H)⁺.

Example 279 (2S, 3S,5S)-1,6-Diphenyl-2,5-[N-(thiophene-3-ylmethyloxycarbonyl)amino]-3-hydroxyhexane

3-Thiophenemethanol (285 mg, 2.5 mmol) was reacted with4-nitrophenylchloroformate (554 mg, 2.75 mmol) by the proceduredescribed in Example 272A to give (thiophen-3-ylmethyl)(4-nitrophenyl)carbonate (598 mg). This compound (170 mg, 0.61 mmol) wasreacted with the compound resulting from Example 1E (57.8 mg, 0. 203mmol) by the procedure described in Example 272B to give, after columnchromatography on silica gel eluting with a gradient (5%,10%,20%) ofethyl acetate in methylene chloride, the title compound. ¹ H NMR(DMSO-d₆, 300 MHz) δ1.50 (m, 2H), 2.54-2.78 (m, 5H), 3.58 (m, 1H), 3.90(m, 3H), 4.67 (d, 1H), 4.85 (m, 1H), 4.91 (m, 4H), 6.84 (d, 1H),6.95-7.33 (m, 16H), 7.49 (m, 2H). Anal calcd for C₃₀ H₃₂ N₂ O₅ S₂ : C,63.83; H, 5.67; N, 4.96. Found: C, 63.74; H, 5.76; N, 4.97. MS (DCI/NH₃)m/e 565 (M+H)⁺, 582 (M+H+NH₃)⁺.

Example 280 (2S,3S,5S)-1,6-Diphenyl-2,5-[N-(thiophene-3-ylmethyloxycarbonyl)amino]-3-hydroxyhexane

This compound was prepared in analogy to ExamplEe 279 starting from2-thiophenemethanol instead of 3-thiophenemethanol. The crude productwas chromatographed on silica gel eluting with a gradient (5%,10%) ethylacetate in methylene chloride to give the title compound. ¹ H NMR(DMSO-d₆, 300 MHz) δ1.48 (m, 2H), 2.53-2.77 (m, 4H), 3.56 (m, 1H), 3.90(m, 2H), 4.63 (d, 1H), 5.00-5.17 (m, 5H), 6.86 (d, 1H), 6.94-7.28 (m,16H), 7.50 (m, 2H). Anal calcd for C₃₀ H₃₂ N₂ O₅ S₂ : C, 63.83; H, 5.67;N, 4.96. Found: C, 63.80; H, 5.74; N, 4.89. MS (DCI/NH₃) m/e 565 (M+H)⁺,582 (M+H+NH₃)⁺.

Example 281 (2S, 3S,5S)-1,6-Diphenyl-2,5-[N-(2-methyl-pyridin-3-ylmethyloxycarbonyl)amino]-3-hydroxyhexane

Methyl 2-methylnicotinate (2.00 g, 12.1 mmol) was reduced to2-methyl-3-pyridinemethanol using lithium aluminum hydride by theprocedure described in Example 274A. This compound was converted to(2-methyl-pyridin-3-ylmethyl) (4-nitrophenyl)carbonate by the procedurealso described in Example 274A. This carbonate (170 mg, 0.59 mmol) wasreacted with the compound resulting from Example 1E (56 mg, 0.0197 mmol)by the procedure described in Example 272B to give, after columnchromatography on silica gel eluting with a gradient (2%,5%) of methanolin methylene chloride, the title compound (63.6 mg). ¹ H NMR (DMSO-d₆,300 MHz) δ1.51 (m, 2H), 2.40 (s, 6H), 2.54-2.75 (m, 5H), 3.60 (m, 1H),3.88 (m, 2H), 4.72 (d, 1H), 4.95 (m, 4H), 7.00 (d, 1H), 7.03-7.28 (m,16H), 7.47 (m, 2H), 8.35 (m, 2H). Anal calcd for C₃₄ H₃₈ N₄ O₅.0.5 H₂ O:C, 69.04; H, 6.60; N, 9.48. Found: C, 68.98; H, 6.48; N, 9.39. MS(DCI/NH₃) m/e 583 (M+H)⁺.

Example 282 (2S, 3S,5S)-1,6-Diphenyl-2,5-[N-(tetrahydrofuran-3-ylmethyloxycarbonyl)amino]-3-hydroxyhexane

3-Tetrahydrofuranmethanol (265 mg, 2.59 mmol) was reacted with4-nitrophenylchloroformate (575 mg, 2.85 mmol) by the proceduredescribed in Example 272A to give (tetrahydrofuran-3-ylmethyl)(4-nitrophenyl)carbonate (585 mg). This compound (155 mg, 0.581 mmol)was reacted with the compound resulting from Example 1E (55 mg, 0.194mmol) to give, after column chromatography on silica gel eluting with agradient (2%,5%) of methanol in methylene chloride, the tire compound(68.8 mg). ¹ H NMR (DMSO-d₆, 300 MHz) δ1.48 (m, 2H), 1.85 (m, 2H), 2.35(m, 2H), 2.54-2.77 (m, 5H), 3.52-3.88 (m, 16H), 4.64 (m, 2H), 6.70 (d,1H), 6.98 (d, 1H), 7.10-7.28 (m, 10H). Anal calcd for C₃₀ H₄₀ N₂ O₇. H₂O: C, 64.52; H, 7.53; N, 5.02. Found: C, 64.87; H, 7.22; N, 5.00. MS(DCI/NH₃) m/e 541 (M+H)⁺, 558 (M+H+NH₃)⁺.

Example 283 (2R,3S,4R)-5-Cyclohexyl-2.4-bis-(N-(N-((benzyloxycarbonyl)valinyl)-amino)-3-hydroxy-1-phenylpentaneA. (4S, 5R)-N-Boc-5-(Cyclohexylmethyl)-4-hydroxy-2-pyrrolidinone.

To a solution of N-Boc-cyclohexylalanine (8.76 g, 32.3 mmole), Meldrum'sacid (4.89 g, 33.9 mmole) and DMAP (9.07 g, 74.2 mmole) in anhydrousdichloromethane (160 mL) at ca. -10° C. was added isopropenylchloroformate (3.80 g, 31.8 mole) in anhydrous dichloromethane (7 mL)dropwise over 35 m. After 2 h at ca. -5° to 0° C. the reaction wasquenched by the addition of cold 5% KHSO₄ solution (200 mL). The layerswere separated and the organics were washed with cold 5% KHSO4 solution(200 mL), then the combined aqueous portions were extracted withdichloromethane (50 mL) and the combined organics were washed with brine(100 mL) and dried (MgSO₄). Solvent evaporation left 12.41 g of thecondensation adduct as a light yellow oil which was dissolved in ethylacetate (350 mL) and heated to reflux for 30 m. The solution was allowedto cool and was extracted with half-saturated sodium bicarbonatesolution (6×200 mL). The combined aqueous portions were carefullyacidified to ca. pH 2 with powdered citric acid. The solution wasextracted with ethyl acetate (3×200 mL) and the combined organics weredried (MgSO₄), filtered and concentrated to give 10.26 g of the(5R)-N-Boc-5-(cyclohexylmethyl)-2,4-pyrrolidindione as a thick yellowoil which was dissolved in dichloromethane (150mL) and glacial aceticacid (20 mL). After chilling to ca. 0° C., sodium borohydride (4.69 g,124 mmole) was added in portions over 1 h. After stirring the resultingmixture for ca. 3 h it was poured into ice water (300 mL) and stirred 10m. The layers were separated and the aqueous portion was extracted withdichloromethane (2×100 mL). The organics were washed once with brine(300 mL) and then dried (Na₂ SO₄). Evaporation left 9.0 g oil which wasapplied to a flash silica gel column (2"×16") and eluted with 50% ethylacetate/hexane, yielding after solvent removal 5.58 g of the desired(4S, 5R)-N-Boc-5-(cyclohexylmethyl)-4-hydroxy-2-pyrrolidinone: R_(f)=0.35 (50% EA/Hx); [α]²¹ _(D) =+40.9° (c=2.1, CHCl₃).

B. (3R, 4S,5R)-N-Boc-3-Benzyl-5-(cyclohexylmethyl)-4-hydroxy-2-pyrrolidinone

To a solution of LDA (prepared from diisopropylamine (0.60 mL, 4.28mmole) and n-BuLi (2.90 mL, 3.97 mole) in THE (6.50 mL)) at -78° C. wasadded dropwise a solution of the resultant compound of Example 283A inTHF (15.0 mL). After 2 h at -78° C., DMPU (0.98 mL, 8.10 mmole) wasadded and after 15 m, benzyl bromide (0.64 mL, 5.38 mmole). The reactionmixture was stirred at -78° C. for ca. 2.5 h and then was allowed towarm slowly to ca. -30° C. over 1.25 h at which point the reaction wasquenched by the addition of 0.1N citric acid solution. The mixture waswarmed to RT and partitioned between water and ether, the layers wereseparated, and the aqueous portion was extracted with ether (2x). Thecombined organics were washed with brine (2x) and then dried (MgSO₄).Flash silica gel chromatography (col. 1"×8"; hexane to 20% ethylacetate/hexane) gave the product 0.482 g; R_(f) =0.35 (1:2 EA/Hx); [α]²⁵_(D) =+41.4° (c=3.01, CHCl₃).

C. (2R, 3S,4R)-4-(N-Boc-amino)-2-benzyl-5-cyclohexyl-3-hydroxy-pentanoic acidacetonide

To a solution of the resultant compound of Example 283B (176 mg, 0.45mmole) in THF (5.0 mL) was added LiOH solution (1.35 mL, 1.35 mmole) andthe resulting mixture was stirred 1.5 h at which point the solvents wereremoved in vacuo and the residue was partitioned between ethyl acetateand 1.0N citric acid solution. The aqueous phase was extracted withethyl acetate (2x) and the combined organics were dried (NaSO₄).Evaporation of solvent left 256 mg residue which was dissolved in CH₂Cl₁₂ (6 mL) and to which was added 2-methoxypropene (0.13 mL, 1.35mmole) and PPTS (ca. 5 mg). After stirring 2 h at RT the mixture wasconcentrated and residue applied to a column of flash silica gel (1"×5";5% to 25% ethyl acetate/hexane) to yield 191.9 mg of the desiredcompound; R_(f) =0.38 (1:2 EA/Hx); [α]²⁰ _(D) =-10.1° (c=0.68, CHCl₃).

D. (2R, 3S,4R)-4-(N-Boc-amino)-2-(N-Cbz-amino)-5-cyclohexyl-3-hydroxy-1-phenylpentaneacetonide

A solution of the resultant compound of Example 283C (176 mg, 395μmole), triethylamine (0.11 mL, 790 μmole), and diphenylphosphoryl azide(0.13 mL, 603 μmole) in dry xylene (1.30 mL) was heated at ca. 50° C.for 1 h, the temperature was increased to ca. 85° C. and DMAP (ca. 10mg) and benzyl alcohol (0.20 mL, 1.93 mmole) were added. The reactionwas stirred 19 h then allowed to cool to RT and evaporated. The residuewas subject to flash chromatography (1"×8"; 10% ethyl acetate/hexane) togive 150.6 mg of the desired compound; R_(f) =0.48 (20% EA/Hx); [α]²⁰_(D) =+2.7° (c=1.11, CHCl₃).

E. (2R, 3S,4R)-4-(N-Boc-amino)-2-amino-5-cyclohexyl-3-hydroxy-1-phenylpentaneacetonide

A mixture of the resultant compound of Example 283D (133 mg, 240 μmole),10% Pd/carbon (0.13 g) and glacial acetic acid (ca. 6 mL) were stirredtogether under an atmosphere of hydrogen for 21 h. After filtration, thesolvent was removed from the filtrate and the residue taken up in CH₂Cl₂ and washed with 1M NaOH. The aqueous phase was extracted twice andthe combined organics were washed with brine (1x) and dried (MgSO₄).Filtration and evaporation left 96.9 mg of the desired product; R_(f)=0.41 (1:2 EA/Hx); [α]²⁰ _(D) =+3.8° (c=1.20, CHCl₃).

F. (2R,3S,4R)-5-cyclohexyl-2,4-diamino-3-hydroxy-1-phenylpentane.

To a solution of the resultant compound of Example 283E (79 mg,189μmole) in MeOH (1.50 mL) at 0° C. was added 4.8M HCl/dioxane (0.40mL, 1.9 mmole). The reaction was stirred ca. 2 h then allowed to warmslowly to RT over ca. 23 h. After flushing the solution with N₂ forseveral minutes, solid sodium carbonate was added and stirred 10 m. Themixture was diluted with CH₂ Cl₂ (ca. 2x volume) and filtered thoughCelite. Evaporation left 80 mg yellow glass which was purified by flashsilica gel chromatography (1/2"×4"; 1:10:89 conc. NH₄ OH/MeOH/CH₂ Cl₂)to give 41 mg desired product; R_(f) =0.05 (7% MeOH/CH₂ Cl₂); [α]²⁰ _(D)=-32.0° (c=0.67, CHCl₃); ¹ H NMR (CDCl₃, 300 MHz) δ0.8-1.45 (m, 8H),1.6-1.85 (m, 5H), 1.9-2.2(br s,5H), 2.50(dd, J=10.5,13.8 Hz, 1H),2.95(dd, J=4,13.8 Hz, 1H), 3.1-3.2(m, 2H), 3.25(t,J=4.5 Hz,1H),7.1-7.4(m, 5H); Mass spectrum: (M+H)+=277; IR spectrum: (CDCl₃) 3390cm⁻¹.

G.(2R,3S,4R)-5-Cyclohexyl-2,4-bis-(N-(N-((benzyloxycarbonyl)-valinyl)-amino)-3-hydroxy-1-phenylpentane.

A solution of (2R, 3S,4R)-5-cyclohexyl-2,4-diamino-3-hydroxy-1-phenylpentane (37.3 mg, 135μmole) and N-(benzyloxycarbonyl)-valine p-nitrophenyl ester (111 mg, 298μmole) in THF (1.3 mL) was stirred at RT for 21/2d. 1M NaOH (ca. 1 mL)was added and the mixture stirred 45 m when it was partitioned betweenethyl acetate and saturated sodium bicarbonate solution. The layers wereseparated and the aqueous portion was saturated with NaCl and extractedwith ethyl acetate (3x). The combined organics were washed with brine(1x) and dried (Na₂ SO₄ and activated carbon). Filtration andevaporation left ca. 150 mg yellow oil which was subject to flashchromatography (1"×6"; 50% ethyl acetate) to give 70 mg desiredcompound; R_(f) =0.42 (1:2 EA/Hx); ¹ H NMR (CDCl₃, 300 MHz) δ0.7-0.9 (m,3H ), 0.68 (d, J=7 Hz, 3H), 0.75 (d ,J=7 Hz,3H), 0.96(d,J=7 Hz,3H),1.00(d,J=7 Hz, 3H), 1.05-1.35 (m, 5H), 1.4-1.8 (m, 4H), 1.9-2.0 (m, 1H),2.30 (dd, J=6, 13.5 Hz, 1H), 2.95(dd, J=9,13.8 Hz,1H), 3.21 (dd, J=3,13.8 Hz, 1H), 3.45-3.55 (m, 1H), 3.55-3.7 (m, 1H), 3.7-3.75 (m, 1H),3.8-3.9 (m, 1H), 4.02 (dd, J=6, 8 Hz, 1H), 4.78 (d, J=9 Hz, 1h),4.95-5.05(m, 4H), 5.05(t,J=12 Hz, 1H), 5.58(d,J=7 Hz, 1H), 6.27(d,J=9Hz, 1H), 6.95(d,J=7 Hz, 1H), 7.1-7.4 (m, 15H); Mass spectrum: (M+NH₄)⁺=760, (M+H)⁺ =743.

Example 284 (2R, 3S,4R)-5-Cyclohexyl-2,4-bis-(N-(N-((2-pyridinyl)methoxycarbonyl)-valinyl)-amino)-3-hydroxy-1-phenylpentane

A solution of the resultant compound of Example 283F (20 mg, 72 μmole),the resultant compound of Example 2D (85 mg, 228 μmole) andtriethylamine (33 μL, 236 μmole) in THF (0.70 mL) was stirred at RT for2 d. The solvents were removed in vacuo and the residue subject to flashchromatography (1/2"×6"; 2% to 5% MeOH/CH₂ Cl₂) to yield 31.5 mg desiredcompound; R_(f) =0.50 (10% MeOH/CH₂ Cl₂); [α]²⁰ _(D) =-19.5° (c=0.80,CHCl₃); ¹ H NMR (CDCl₃, 300 MHz) δ0.7-1.3 (m, 3H), 0.68 (d, J=7 Hz, 3H),0.78 (d, J=7 Hz, 3H), 0.98 (d, J=7 Hz, 3H), 1.00 (d, J=7 Hz, 3H),1.4-1.5 (m, 1H), 1.5-1.85 (m, 9H), 2.05 (dd, J=6, 13 Hz, 1H), 2.3-2.4(m, 1H), 2.9 5 (dd, 9, 13.8 Hz, 1H), 3.18 (d, J=13.8 Hz, 1H), 3.5-3.65(m, 2H), 3.8 2 (t, J=3 Hz, 1H), 3.85-3.95 (m, 1H), 4.06 (dd, J=5.4,7.5Hz, 1H), 4.7-4.8 (m, 1H), 5.1-5.3(m, 5H), 5.73(d,J=7.5 Hz,1H), 6.37(d,J=9 Hz, 1H), 6.90 (d, J=6 Hz, 1H), 7.1-7.4 (m, 9H), 7.6-7.8 (m, 2H),8.5-8.6 (m, 2H); Mass spectrum: (M+H)⁺ =745; Anal. Calcd for C₄₁ H₅₆ N₆O₇.1/2H₂ O: C,65.32; H,7.62; N,11.15. Found: C,65.32; H, 7.54; N, 11.10.

Example 285 (2R, 3S,4R)-2,4-Bis-(N-(N-((2-pyridinyl)methoxycarbonyl)-valinyl)-amino)-3-hydroxy-1-(2-napthyl)-5-phenylpentane A.(4S,5R)-N-Boc-5-Benzyl-4-hydroxy-2-pyrrolidinone

Using the procedure of Example 283A but with N-Boc-phenylalaninereplacing N-Boc-cyclohexylalanine the desired compound was provided.

B. (3R, 4S,5R)-N-Boc-5-benzyl-4-hydroxy-3-(2-napthylmethyl)-2-pyrrolidinone

To a solution of LDA (prepared from diisopropylamine (0.68 mL, 4.85mmole) and n-BuLi (3.45 mL, 4.66 mmole) in THF (8.0 mL)) at 0° C. wasadded HMPA (1.29 mL, 7.41 mole); chilled to -78° C. and added theresultant compound of Example 285A (0.540 g, 1.85 mmole) in THF (7.0mL). After 50 m a solution of 2-(bromomethyl)napthalene in THF (5.0 mL)was added and the reaction was stirred at -78° C. for 30 m before it wasquenched by the addition of 1.0N citric acid solution. The mixture wasdiluted with ether(100 mL) and washed with 1.0N citric acid solution(2×50 mL). The aqueous portions were extracted with ether (1×50 mL) anddiscarded. The combined organics were washed with brine (3×50 mL) anddried (MgSO₄). Evaporation and flash silica gel chromatography (1"×12";hexane to 20% ethyl acetate/hexane) gave 0.28 g desired compound; R_(f)=0.39 (1:2 EA/Hx); [α]²⁵ _(D) =-4.4° (c=0.59, CHCl₃).

C.(2R.3S,4R)-4-(N-Boc-amino)-3-hydroxy-2-(2-napthylmethyl)-5-phenylpentanoicacid acetonide

Using the procedure of Example 283C but with the resultant compound ofExample 285B (0.23 g, 0.53 mmole) replacing the resultant compound ofExample 283B, 0.21 g of the desired compound was obtained; R_(f) =0.61(50% EA/Hx).

D. (2R,3S,4R)-4-(N-Boc-amino)-2-(N-Cbz-amino)-3-hydroxy-1-napthyl)-5-phenylpentaneacetonide

Using the procedure of Example 283D but with the resultant compound ofExample 285C (203 mg, 414 μmole) replacing the resultant compound ofExample 283C, 187 mg of the desired compound was obtained; R_(f) =0.36(20% EA/Hx); ¹ H NMR (CDCl₃, 300 MHz) δ1.36(s,3H), 1.53(s,9H), 1.75 (S,3H), 2.6-2.9 (m, 2H), 3.05-3.30 (m, 2H), 3.7-4.2 (m, 4H), 4.8-5.0 (m,2H), 7.0-7.3 (m, 11H), 7.4-7.5 (m, 3H), 7.65-7.8 (m, 3H); Mass spectrum:(M+NH₄)⁺ =612, (M+H)⁺ =595.

E. (2R,3S,4R)-2-amino-4-(N-Boc-amino)-3-hydroxy-1-(2-napthyl)-5-phenylpentaneacetonide

Using the procedure of Example 283E but with the resultant compound ofExample 285D (180 mg, 303 μmole) replacing the resultant compound ofExample 283D, 119 mg of the desired compound was obtained; R_(f) =0.06(EA/Hx); ¹ H NMR (CDCl₃, 300 MHz) δ1.33(s,3H), 1.54(s,9H), 1.6-1.7(m,2H), 1.75(s,3H), 2.3-2.5(m, 1H), 2.6-2.8(m, 1H), 2.85-2.95(m, 1H),3.1-3.2 (m, 1H), 3.2-3.3 (m, 1H), 3.7-3.85 (m, 1H), 4.1-4.25 (m, 1H),7.15-7.3 (m, 6H), 7.4-7.5 (m, 2H), 7.53 (s, 1H), 7.7-7.9 (m, 3H); Massspectrum: (M+H)⁺ =460.

F. (2R, 3S,4R)-2,4-diamino-3-hydroxy-1-(2-napthyl)-5-phenylpentane

Using the procedure of Example 283F but with the resultant compound ofExample 285E (114 mg, 248 μmole) replacing the resultant compound ofExample 283E, 111 mg of the desired compound was obtained; R_(f) =0.28(1:10:89 conc. NH₄ OH/MeOH/CH₂ Cl₂); Mass spectrum: (M+H)⁺ =321.

G. (2R, 3S,4R)-2,4-Bis-(N-(N-((2-pyridinyl)methoxycarbonyl)valinyl)-amino)-3-hydroxy-1-(2-napthyl)-5-phenylpentane

Using the procedure of Example 284A but with the resultant compound ofExample 285F (58.5 mg, 182 μmole) replacing the resultant compound ofExample 283F, 80 mg of the desired compound was obtained; R_(f) =0.50(10% MeOH/CH₂ Cl₂); ¹ H NMR (CDCl₃, 300 MHz) δ0.53 (d, J=7 Hz, 3H), 0.66(d, J=7 Hz, 3H), 0.93 (d, J=7 Hz, 6H), 1.65-2. 0 (m, 4H), 2.2-2.4 (m,1H), 3.0-3.2 (m, 3H), 3.3-3.4 (m, 1H), 3.5-3.8 (m, 3H), 4.05-4.15(m,1H), 5.00(s, 1H), 5.05-5.25(m, 4H), 5.74(d, J=9 Hz, 1H), 6.28(d,J=7.5Hz,1H), 7.0-7.5(m, 12H), 7.55-7.8(m, 6H). 8.4-8.6 (m, 2H); Mass spectrum(FAB): (M+Na)⁺ =811, (M+H)⁺ =789.

Example 286 (2R, 3S,4R)-2,4-Bis-(N-(N-((2-pyridinyl)methoxycarbonyl)valinyl)-amino)-3-hydroxy-1-(1-napthyl)-5-phenylpentaneA. (3R,4S,5R)-N-Boc-5-benzyl-4-hydroxy-3-(1-napthylmethyl)-2-pyrrolidinone

Using the procedure of Example 285B with the resultant compound ofExample 285A (0.694 g, 2.38 mole) but replacing 2-(bromomethyl)napthalene with 1-(bromomethyl) napthalene, 0.440 g of the desiredcompound was obtained; R_(f) =0.39 (1:2 EA/Hx); [α]²⁵ _(D) =+36.3°(c=2.59, CHCl₃).

B. (2R, 3S,4R)-4-(N-Boc-amino)-3-hydroxy-2-(1-napthylmethyl)-5-phenylpentanoic acidacetonide

Using the procedure of Example 283C but with the resultant compound ofExample 286A (0.46 g, 1.08 mmole) replacing the resultant compound ofExample 283B, 319 mg of the desired compound was obtained: R_(f) =0.34(1:2 EA/Hx); [α]²⁴ _(D) =-53.4° (c=2.6, CHCl₃).

C. (2R, 3S,4R)-4-(N-Boc-amino)-2-(N-Cbz-amino)-3-hydroxy-1-napthyl)-5-phenylpentaneacetonide.

Using the procedure of Example 283D but with the resultant compound ofExample 286B (131 mg, 264 μmole) replacing the resultant compound ofExample 283C, 119 mg the desired compound was obtained: R_(f) =0.38 (20%EA/Hx); [α]²⁴ _(D) =-73.7° (c=2.6, CHCl₃).

D. (2R, 3S,4R)-4-(N-Boc-amino)-2-amino-3-hydroxy-1-(1-napthyl)-5-phenylpentaneacetonide

Using the procedure of Example 283E but with the resultant compound ofExample 286C (233 mg, 392 μmole) replacing the resultant compound ofExample 283D, 140 mg of the desired compound was obtained: R_(f) =0.52(1:2 EA/Hx); [α]²⁴ _(D) =-60.6° (c=1.04, CHCl₃).

E. (2R, 3S, 4R)-2,4-diamino-3-hydroxy-1-(1-napthyl)-5-phenylpentane

Using the procedure of Example 283F but with the resultant compound ofExample 286D (116 mg, 251 μmole) replacing the resultant compound ofExample 283E, 51.3 mg of the desired compound was obtained: R_(f) =0.14(1:10:89 conc. NH₄ OH/MeOH/CH₂ Cl₂); [α]²⁰ _(D) =-33.5° (c=1.07, CHCl₃);¹ H NMR (CDCl₃, 300 MHz) δ2.1(br s,5H), 2.72(dd, J=10,14 Hz, 1H), 2.82(dd, J=10.5, 14.8 Hz, 1H), 2.96 (dd, J=6, 14 Hz, 1H), 3.28(ddd, J=3,6,10Hz, 1H), 3.45(m,2H), 3.63(dd, J=3,14 Hz,1H), 7.2-7.55(m, 9H), 7.74(d,J=9Hz,1H), 7.8-7.9(m, 1H), 8.0-8.1 (m, 1H); Mass spectrum: (M+H)⁺ =321; IRspectrum: (CDCl₃) 3390, 3020, 1590 cm⁻¹.

F. (2R, 3S,4R)-2,4-Bis-(N-(N-((2-pyridinyl)methoxycarbonyl)valinyl)-amino)-3-hydroxy-1-(1-napthyl)-5-phenylpentane

Using the procedure of Example 284A but with the resultant compound ofExample 286E (45 mg, 140 μmole) replacing the resultant compound ofExample 283E, 77.7 mg of the desired compound was obtained: R_(f) =0.32(5% MeOH/CH₂ Cl₂); [α]²⁰ _(D) =-54.8° (c=2.14, CHCl₃); ¹ H NMR (CDCl₃, 300 MHz) δ0.47 (d, J=6 Hz, 3H), 0.67 (d, J=6 Hz, 3H), 0.79(d,J=6 Hz, 3H),0.86 (d, J=6 Hz, 3H), 1.92 (dd, J=7,12.6 Hz, 1H), 2.25 (dd, J=7,12 Hz,1H), 2 69 (br s, 1H), 3.12 (d, J=7 Hz, 2H), 3.27 (dd, J=9, 13.8 Hz, 1H),3.7-3.9 (m, 3H), 3.95-4.15 (m, 2H ), 4.85-5.3 (m, 5H), 5.64 (d, J=8 Hz,1H), 6.37 (d, J=9 Hz, 1H), 7.1-7.35(m, 13H), 7.4-7.5(m, 2H), 7.55-7.7(m,3H), 7.75 (d, J=7.5 Hz, 1H), 8.13 (d, J=9 Hz, 1H), 8.53 (br s, 2H); Massspectrum: (M+H)⁺ =789; IR spectrum: (CDCl₃) 3420, 3140, 1720, 1660, 1510cm⁻¹ ; Anal. Calcd for C₄₅ H₅₂ N₆ O₇.H₂ O: C,66.98; H, 6.74; N,10.41.Found: C,66.69; H,6.51; N,10.29.

Example 287(2R.3S,4R)-2,4-Bis-(N-(N-((2-pyridinyl)methoxycarbonyl)valinyl)-amino)-3-hydroxy-5-(1-napthyl)-1-phenylpentaneA. (4S, 5R)-N-Boc-4-hydroxy-5-(1-napthylmethyl)-2-pyrrolidinone

Using the procedure of Example 283A but with N-Boc-(1-napthyl)alaninereplacing N-Boc-cyclohexylalanine the desired compound was provided;R_(f) =0.77 (2:3:95 HOAc/MeOH/EA) and 0.04 (1:1:2 ether/CH₂ Cl₂ /Hx);[α]²⁴ _(D) =-59.5° (c=2.6, CHCl₃).

B.(3R,4S,5R)-N-Boc-3-benzyl-4-hydroxy-5-(1-napthylmethyl)-2-pyrrolidinone

Using the procedure of Example 285B with the resultant compound ofExample 287A (0.708 g, 2.07 mmole) but replacing2-(bromomethyl)napthalene with benzyl bromide, 0.497 g of the desiredcompound was obtained; R_(f) =0.25 (1:1:2 ether/CH₂ Cl₂ /Hx); [α]²⁰ _(D)=-17.4° (c=1.21, CHCl₃).

C. (2R,3S,4R)-4-N-Boc-amino)-2-benzyl-3-hydroxy-5-napthyl) pentanoicacid acetonide

Using the procedure of Example 283C but with the resultant compound ofExample 287B (0.41 g, 0.95 mmole) replacing the resultant compound ofExample 283B, 190 mg of the desired compound was obtained; R_(f) =0.25(1;2 EA/Hx); [α]²⁰ _(D) =-41.3° (c=0.15, CHCl₃).

D.(2R,3S,4R)-4-(N-Boc-amino)-2-(N-Cbz-amino)-3-hydroxy-5-(1-napthyl)-1-phenylpentaneacetonide

Using the procedure of Example 283D but with the resultant compound ofExample 287C (155 mg, 317 μmole) replacing the resultant compound ofExample 283C, 152 mg of the desired compound was obtained; R_(f) =0.36(20% EA/Hx); [α]²⁰ _(D) =-58.4° (c=2.16, CHCl₃).

E.(2R,3S,4R)-2-amino-4-(N-Boc-amino)-3-hydroxy-5-(1-napthyl)-1-phenylpentaneacetonide

Using the procedure of Example 283E but with the resultant compound ofExample 287D (140 mg, 230 μmole) replacing the resultant compound ofExample 283D, 49.1 mg of the desired compound was obtained; R_(f) =0.22(1:2 EA/Hx); [α]²⁰ _(D) =-62.2° (c=0.83, CHCl₃).

F. (2R,3S,4R)-2,4-diamino-3-hydroxy-5-(1-napthyl)-1-phenylpentane

Using the procedure of Example 283F but with the resultant compound ofExample 287E (40 mg, 87 μmole) replacing the resultant compound ofExample 283E, 21.2 mg of the desired compound was obtained; R_(f) =0.32(1:15:84 conc. NH₄ OH/MeOH/CH₂ Cl₂); [α]²⁰ _(D) =-6.8° (c=0.56, CHCl₃);¹ H NMR (CDCl₃, 300 MHz) δ2.15(br s,5H), 2.5 4 (dd, J=9, 13.5 Hz, 1H),2.94(dd,J=4,13.5 Hz, 1H), 3.13(dd, J=9,14 Hz,1H), 3.23(ddd, J=4,5.4,9Hz,1H), 3.42(dd, J=5.4,14 Hz, 1H), 3.48(dd, J=2.4,5.4 Hz, 1H), 3.57(ddd,J=2.4,5.4,9 Hz,1H), 7.1-7.6 (m, 9H), 7.76 (d, J=8.7 Hz, 1H), 7.85-7.9(m, 1H), 8.06 (d, J=8.7 Hz, 1H); Mass spectrum: (M+H)⁺ =321; IRspectrum: (CDCl₃) 3380, 3320, 1595 cm⁻¹.

G.(2R,3S,4R)-2,4-Bis-(N-(N-((2-pyridinyl)methoxycarbonyl)-valinyl)-amino)-3-hydroxy-5-(1-napthyl)-1-phenylpentane

Using the procedure of Example 284A but with the resultant compound ofExample 287F (18 mg, 56 μmole) replacing the resultant compound ofExample 283F, 20 mg of the desired compound was obtained; R_(f) =0.31(5% MeOH/CH₂ Cl₂); [α]²⁰ _(D) =-34.9° (c=0.37, CHCl₃); ¹ H NMR (CDCl₃,300 MHz) δ0.58 (d, J=7 Hz, 3H), 0.68 (d, J=7 Hz, 3H), 0.85(d,J=7 Hz,3H),0.93(d,J⁼ 7 Hz,3H), 1.85-2.0(m, 1H), 2.31 (dd, 6,12 Hz, 1H), 2.87(dd,J=9,13.5 Hz,1H), 3.20(d,J=13.5 Hz, 1H), 3.5-3.9 (m, 6H), 3.95-4.1 (m,1H), 4.12 (dd, J=5.4,9 Hz, 1H), 4.7-4.9 (m, 2H), 5.0-5.2(m, 2H),5.15(s,2H), 5.68(d,J=9Hz, 1H), 6.17 (d, J=8 Hz,1H), 7.0-7.45(m, 12H),7.48(t,J=7.5Hz, 1H), 7.55-7.7 (m,3H), 7.75 (d, J=8 Hz, 1H), 8.04 (d, J=9Hz, 1H), 8.45 (d, J=4 Hz, 1H), 8.55 (d, J=4 Hz, 1H); Mass spectrum:(M+H)⁺ =789; Anal. Calcd for C₄₅ H₅₂ N₆ O₇.H₂ O: C, 66.98; H,6.74;N,10.41. Found: C,66.77; H,6.66; N,10.01.

Example 288 (6-Methylpyridin-2-yl)methoxycarbonyl-Valine

To a solution of the isocyanate derived from Valine methyl ester (17.9mmol) dissolved in toluene was added 6-methyl-pyridine-2-methanol (2.42g, 1.1 equivalent). The solution was heated at reflux for 2 hours. Afterconcentration in vacuo and purifiction by silica gel columnchromatography, (6-methylpyridin-2-yl)methoxycarbonyl-Valine methylester (2.8 g) was obtained. Hydrolysis of the methyl ester using aqueouslithium hydroxide provide the title compound upon recrystallization fromhot ethyl acetate.

Example 289(2S,3S,5S)-2-(N-[(6-Methylpyridin-2-yl)methoxycarbonyl-Valyllamino)5-(N-[(pyridin-3-yl]methoxycarbonyl]amino)-1.6-diphenyl-3-hydroxyhexane

Coupling of the resultant compound from Example 288 with (2S, 3S,5S)-2-amino-5-(N-[(pyridin-3-yl)methoxycarbonyl]amino)-1,6-diphenyl-3-hydroxyhexane using standard EDAC/HOBT methodology afforded the title compoundin 79% yield. m.p. 175°-176° C. ¹ H NMR (DMSO-d₆, 300 MHz) δ0.73 (d,3H), 0.78 (d, 3H), 1.50 (m, 2H), 1.90 (m, 1H), 2.45 (s, 3H), 2.60-2.70(m, 4H), 3.55 (m, 1H), 3.85 (m, 2H), 4.95 (ABq, 2H), 5.05 (s, 2H),7.10-7.20 (m, 12H), 7.35 (m, 2H), 7.49 (d, 1H), 7.55 (d, 1H), 7.70 (t,1H), 8.50 (m, 2H). MS (DCI/NH₃) m/e 668 (M+H)⁺.

Example 290(2S,3S,5S)-2-(N-[(pyridin-3-yl)methoxycarbonyl]amino)-5-(N-[(6-methylpyridin-2-yl)methoxycarbonyl-valyllamino)-1,6-diphenyl-3-hydroxyhexane

Coupling of the resultant compounds from Example 288 with (2S, 3S,5S)-2-(N-[(pyridin-3-yl-methoxycarbonyl]amino)-5-amino-1,6-diphenyl-3-hydroxyhexaneusing standard EDAC/HOBt methodology afforded the title compound in 70%yield. ¹ H NMR (DMSO-d₆ ; 300 MHz): δ0.75 (d, 3H), 0.78 (d, 3H), 2.45(s, 3H), 4.60 (d, 1H), 4.95 (m, 2H), 5.05 (s, 2H), 7.05-7.70 (m, 15H),8.50 (m, 2H). Mass spectrum: (M+H)⁺ =668.

Example 291 [(6-Methylpyridin-3-yl]methyl](4-nitrophenyl)carbonate

To a solution of 4-nitrophenylchloroformate (2.00 g) dissolved inmethylene chloride (20 mL) and cooled to 0° C. was added(6-methylpyridin-3-yl)methanol (1 equivalent) and triethylamine (1equivalent). The solution was allowed to warm to room temperature andstirred for 0.5 hours, diluted with methylene chloride, washed withsaturated sodium bica4rbonate solution, dired over sodium sulfate andconcentrated in vacuo. The residue obtained was column chromatographedon silica gel to afford the title compound (80%).

Example 292 [(6-Methylpyridin-3-yl)methoxycarbonyl-Valine

To a solution of the resultant compound from Example 291 (2.00 g)dissolved in dimethylformamide (20 mL) was added Valine methyl esterhydrochloride (1 equivalent) and triethylamine (2 equivalents). Afterstirring at room temperature for 1 hour, the solvent was removed invacuo. The residue obtained was chromatographed on silica gel elutingwith 5% methanol in methylene chloride to afford the title compoundmethyl ester. Hydrolysis with lithium hydroxide in aqueous dioxaneafforded the title compound.

Example 293 (2S, 3S,5S)-2-(N-[(6-Methylpyridin-3-yl)methoxycarbonyl-valyllamino)-5-(N-[(pyridin-3-yl)methoxycarbonyl]amino-1,6-diphenyl-3-hydroxyhexane

Coupling of the resultant compound from Example 292 with (2S, 3S,5S)-2-amino-5-(N-[(pyridin-3-yl)methoxycarbonyl]amino-1,6-diphenyl-3-hydroxyhexaneusing standard EDAC/HOBt methodology afforded the title compound. ¹ HNMT (DMSO-d₆ ; 300 MHz): δ0.70 (d, 3H), 0.75 (d, 3H), 2.45 (s, 3H), 4.90(m, 3H), 5.03 (s, 2H) 7.10-7.65 (m, 16H), 8.45 (m, 2H). Mass spectrum:(M+H)⁺ =668.

Example 294 (2S,3S,5S)-2-(N-[(Pyridin-3-yl]methoxycarbonyl]amino-5-(N-[(6-methyl-pyridin-3-yl]methoxycarbonyl-Valyl]amino)-1,6-diphenyl-3-hydroxyhexane

Coupling of the resultant compound from Example 292 with(2S,3S,5S)-2-(N-[(pyridin-3-yl)methxoycarbonyl]amino-5-amino-1,6-diphenyl-3-hydroxyhexaneusing standard EDAC/HOBt methodology afforded the title compound. ¹ HNMR (DMSO-d₆ ; 300 MHz): δ0.73 (d, 3H), 0.75 (d, 3H), 1.80 (m, 1H), 2.45(s, 3H), 4.67 (d, 1H), 4.96 (m, 2H), 5.05 (s, 2H), 6.90 (br d, 1H),7.05-7.70 (m, 16H), 8.47 (m, 3H). Mass spectrum: (M+H)⁺ =668.

Example 295 A. (2R,5R)-2,5-Diamino-1,6-diphenylhexane

A mixture of 200 mg (0.75 mmol) of the resultant compound of Example 18Band 20 mg of 10% Pd/C in 5 ml of methanol was stirred under 1 atmosphereof H₂ for 16 h. The resulting mixture was filtered and concentrated invacuo to provide the desired compound.

B.(2R,5R)-2,5-Bis-(N-(N-((N-methyl-N-((2-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-1,6-diphenylhexane

Using the procedure of Example 85 but replacing the resultant compoundof Example 4A with the resultant compound of Example 295A and replacingthe resultant compound of Example 43B with the resultant compound ofExample 3F provided, after silica gel chromatography using first 2% then3.5% methanol in chloroform, 17 mg (55%) of the desired compound (R_(f)0.34, 10% methanol in chloroform) as a white solid. Mass spectrum:(M+1)⁺ =763.

Example 296

A. 1-Iodo-2-(iodomethyl)-2-propene

A mixture of 4 ml (3.5 mmol) of 1-chloro-2-(chloromethyl)-2-propene and15 g of sodium iodide in 50 ml of acetone was heated at reflux for 5 h.The resulting mixture was filtered, concentrated in vacuo, taken up indichloromethane, washed sequentially with aqueous NaHSO₃ and water,dried over MgSO₄ and concentrated in vacuo to provide 7.2 g (68%) of thecrude desired compound as an oil.

B.(2R,5R,4'R,5'S)-2,5-Bis-((4-methyl-2-oxo-5-phenyloxazolidinyl)carbonyl)-1,7-diphenyl-4-methyleneheptane

A solution of 1.36 ml of dry diisopropylamine (9.7 mmol) in 30 ml ofanydrous tetrahydrofuran was cooled under N₂ to -78°, treated with 6 ml(9.7 mmol) of n-butyllithium, allowed to warm for 10 min, recooled,treated with 3.0 g (9.7 mmol) of (4R,5S)-3-dihydrocinnamoyl-4-methyl-5-phenyloxazolidin-2-one, stirred at-78° C. for 30 min, treated with 1.5 g of the resultant compound ofExample 296A in 5 ml of tetrahydrofuran, and stirred at -40° C. for 16h. The resulting solution was quenched with aqueous NH₄ Cl, extractedwith dichloromethane, dried over MgSO₄, and concentrated in vacuo.Silica gel chromatography of the residue using 10%-20% ethyl acetate inhexane provided 2.0 g (60%) of the desired compound.

C. (2R,5R)-1,7-Diphenyl-4-methyleneheptane-2,5-dicarboxylic Acid

A solution of 2.0 g (3 mmol) of the resultant compound of Example 296Bin 60 ml of 1:1 tetrahydrofuran:water was cooled to 0° C. and treatedwith a mixture of 19 ml of 0.5M LiOH and 4.5 ml of 30% hydrogenperoxide. The resulting solution was allowed to stand for 20 h, treatedwith aqueous NaHSO₃, stirred for 1 h, concentrated in vacuo, basifiedwith 1N NaOH, washed with ethyl acetate, acidified with 6N HCl, andextracted with chloroform. The organic phase was dried over Na₂ SO₄ andconcentrated to provide 0.9 g (86%) of the crude desired compound.

D.(2R,5R)-2,5-Bis-(N-(benzyloxycarbonyl)amino)-1.7-diphenyl-4-methyleneheptane

A solution of 600 mg (1.7 mmol) of the resultant compound of Example296C, 0.73 ml (3.4 mmol) of diphenylphosphorylazide, and 0.47 ml (3.4mmol) of triethylamine in 6 ml of toluene was heated at reflux for 3 h,treated with 0.7 ml (6.8 mmol) of benzyl alcohol, and heated for anadditional 2 h. The resulting solution was concentrated in vacuo, takenup in dichloromethane, washed with saturated brine, dried over MgSO₄,and concentrated in vacuo. Silica gel chromatography using firstchloroform then 10% ethyl acetate in chloroform provided 302 mg (32%) ofthe desired compound.

E. (2R.5R)-2,5-Bis-(N-(benzyloxycarbonyl)amino)-1,7-diphenylheptan-4-one

A solution of 50 mg (0.09 mmol) of the resultant compound of Example296D in 1 ml of dioxane and 0.3 ml of water was treated with 0.0055 mlof 4% osmium tetroxide in water. After 10 min, 41 mg of sodium periodatewas added, and the mixture was stirred for 1.5 h, treated with 10%aqueous NaHSO₃, stirred for 15 min, and extracted with ethyl acetate.The organic phase was dried over MgSO₄ and concentrated in vacuo toprovide the crude desired compound.

F.(2R,5R)-2,5-Bis-(N-(benzyloxycarbonyl)amino)-1,7-diphenyl-4-hydroxyheptane

The crude resultant compound of Example 296E (40 mg) was suspended in 4ml of methanol, treated with 5.5 mg of sodium borohydride, stirred for45 min, treated with saturated brine, stirred for 10 min, and extractedwith dichloromethane. The organic phase was dried over MgSO₄ andconcentrated in vacuo. Silica gel chromatography using 25%-30% ethylacetate in hexane provided 14.2 mg of the desired compound. Massspectrum: (M+H)⁺ =567.

Example 297(2S,3S-5S)-2-(N-(N-((N-Methyl-N-((6-methyl-2-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-5-(N-((3-pyridinyl)-methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Coupling of(N-((N-methyl-N-((6-methyl-2-pyridinyl)methyl)amino)carbonyl)valine with(2S, 3S,5S)-2-amino-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneusing standard EDAC/HOBt methodology provided the desired compound in91% yield. ¹ H NMR (DMSO-d₆ ; 300 MHz) δ0.72 (d, 3H), 0.77 (d, 3H), 1.92(m, 1H), 2.43 (s, 3H), 2.88 (s, 3H), 4.43 (s, 2H), 4.92 (m, 2H), 6.37(br d, 1H), 7.0-7.65 (m, 15H), 8.50 (m, 2H). Mass spectrum: (M+H)⁺ =681.

Example 298 (2S, 3S,5S)-2-(N-((3-Pyridinyl)-methoxycarbonyl)amino-5-(N-(N-((N-Methyl-N-((6-methyl-2-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-1,6-diphenyl-3-hydroxyhexane

Coupling of(N-((N-methyl-N-((6-methyl-2-pyridinyl)methyl)amino)carbonyl)valine with(2S,3S,5S)-2-(N-((3-pyridinyl)methoxy-carbonyl)amino)-5-amino-1,6-diphenyl-3-hydroxyhexaneusing standard EDAC/HOBt method provided the desired compound in 88%yield. ¹ H NMR (DMSO-d₆ ; 300 MHz); δ0.74 (d, 6H), 2.45 (s, 3H), 2.88(s, 3H), 4.42 (br s, 2H), 4.60 (d, 1H), 4.95 (m, 2H), 6.27 (br d, 1H),6.87 (br d, 1H), 7.10-7.70 (m, 15H), 8.50 (m, 2H). Mass spectrum: (M+H)⁺=681.

Example 299 (2S, 3S,5S)-2-(N-((5-Methyl-3-pyridinyl)methoxycarbonyl)valinyl)amino)-5-(N-(3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Coupling of (5-methyl-3-pyridinyl)methoxycarbonyl)valine with(2S,3S,5S)-2-amino-5-(N((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneusing standard EDAC/HOBt method provided the desired compound in 82%yield. ¹ H NMR (DMSO-d₆ ; 300 MHz): δ0.72 (d, 3H), 0.75 (d, 3H), 1.50(m, 2H), 1.90 (m, 1H), 2.28 (s, 3H), 4.88 (br d, 1H), 4.92 (m, 2H), 5.04(s, 2H), 7.10-7.58 (m, 15H), 8.35 (m, 2H), 8.45 (m, 2H). Mass spectrum:(M+H)⁺ =668.

Example 300 (2S,3S,5S)-2-(N((3-Pyridinyl)methoxycarbonyl)amino)-5-(N((5-methyl-3-pyridinyl)methoxycarbonyl)valinyl)amino)-1,6-diphenyl-3-hydroxyhexane

Coupling of (5-methyl-3-pyridinyl)methoxycarbonyl-valine with (2S, 3S,5S)-2-(N-((3-pyridinyl)methoxycarbonyl)amino)-5-amino-1,6-diphenyl-3-hydroxyhexaneusing standard EDAC/HOBt method provided the desired compound in 80%yield. ¹ H NMR (DMSO-d₆ ; 300 MHz): δ0.73 (d, 3H), 0.77 (d, 3H), 1.45(m, 2H), 1.80 (m, 1H), 2.29 (s, 3H), 4.63 (br d, 1H), 4.95 (m, 2H), 5.05(s, 2H), 6.90 (br d, 1H), 7.10-7.60 (m, 15H), 7.70 (br d, 1H), 8.37 (m,2H), 8.50 (m, 2H). Mass spectrum: (M+H)⁺ =668.

Example 301 (2S, 3S,5S)-2-(N-(N-((N-Methyl-N((6-methyl-3-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-5-(N-((3-pyridinyl)-methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Coupling of (N-((N-Methyl-N-((6-methyl-3-pyridinyl)methyl)amino)carbonyl)valine with (2S, 3S,5S)-2-amino-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneusing standard EDAC/HOBt methodology provided the desired compound in85% yield. ¹ H NMR (DMSO-d₆ ; 300 MHz): δ0.70 (d, 3H), 0.76 (d, 3H),1.50 (m, 2H), 1.90 (m, 1H), 2.40 (s, 3H), 2.79 (s, 3H), 4.40 (m, 2H),4.85 (br d, 1H), 4.92 (m, 2H), 6.0 (br d, 1H), 7.10-7.55 (m, 15H), 8.30(d, 1H), 8.50 (m, 2H). Mass spectrum: (M+H)⁺ =681.

Example 302 (2S, 3S,5S)-2-(N((3-Pyridinyl)methoxycarbonyl)amino)-5-(N-(N-((N-methyl-N-((6-methyl-3-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-1,6-diphenyl-3-hydroxyhexane

Coupling of (N-((N-Methyl-N-((6-methyl-3-pyridinyl)methyl)amino)carbonyl)valine with (2S, 3S, 5S)-2-(N((3-pyridinyl)methoxy-carbonyl)amino)-5-amino-1,6-diphenyl-3-hydroxyhexaneusing standard EDAC/HOBt method provided the desired compound in 83%yield. ¹ H NMR (DMSO-d₆ ; 300 MHz): δ0.72 (d, 3H), 0.75 (d, 3H), 1.48(m, 2H), 1.88 (m, 1H), 2.40 (s, 3H), 2.78 (s, 3H), 4.42 (s, 2H), 4.70(d, 1H), 4.96 (m, 2H), 5.85 (d, 1H), 6.90 (d, 1H), 7.10-7.58 (m, 16H),7.70 (d, 1H), 8.30 (d, 1H), 8.50 (m, 2H). Mass spectrum: (M+H)⁺ =681.

Example 303(2S,3S,5S)-2-(N-(N-((N-(6-methyl-2-pyridinyl)methyl)amino)carbonyl)valinyl)amino-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Coupling of (N-((6-methyl-2-pyridinyl)methyl)amino) carbonyl)valine with(2S, 3S,5S)-2-amino-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneusing standard EDAC/HOBt method provided the desired compound. ¹ H NMR(DMSO-d₆ ; 300 MHz): δ0.74 (d, 3H), 0.80 (d, 3H, 1.50 (m, 2H), 1.90 (m,1H), 2.45 (s, 3H), 4.25 (m, 2H), 4.83 (d, 1H), 4.92 (m, 2H), 6.20 (d,1H), 6.65 (t, 1H), 7.05-7.60 (m, 15H), 8.50 (m, 2H). Mass spectrum:(M+H)⁺ =667.

Example 304 (2S, 3S,5S)-2-(N-((3-Pyridinyl)-methoxycarbonyl)amino)-5-((N-((N-6-methyl-2-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-1,6-diphenyl-3-hydroxyhexane

Coupling of N-((N-((6-methyl-2-pyridinyl)methyl)amino)carbonyl)valinewith (2S, 3S,5S)-2-(N((3-pyridinyl)methoxy-carbonyl)amino)-5-amino-1,6-diphenyl-3hydroxyhexaneprovided the desired compound in 80% yield. ¹ H NMR (DMSO-d₆ ; 300 MHz):δ0.72 (d, 3H), 0.78 (d, 3H), 1.45 (m, 2H), 1.80 (m, 1H), 2.44 (s, 3H),4.25 (d, 2H), 4.63 (d, 1H), 4.95 (m, 2H), 6.15 (d, 1H), 6.65 (t, 1H),6.88 (d, 1H), 7.05-7.60 (m, 15H), 7.27 (d, 1H), 8.50 (m, 2H). Massspectrum: (M+H)⁺ =667.

Example 305 (2S,5S)-Bis-(N((6-methyl-2-pyridinyl)methoxycarbonyl)valinyl)amino)-1,6-diphenyl-3,3-difluoro-4(R)-hydroxyhexane

Coupling of N-((6-methyl-2-pyridinyl)methoxycarbonyl)valine with (2S,5S)-diamino-1,6-diphenyl-3,3-difluoro-4(R)hydroxyhexane using standardEDAC/HOBt methodology provided the desired compounds in 70% yield. ¹ HNMR (DMSO-d₆ ; 300 MHz): δ0.62-0.73 (m, 12H), 2.47 (s, 3H), 2.48 (s,3H), 3.80 (m, 4H), 5.03 (s, 2H), 5.04 (s, 2H), 6.10 (br d, 1H), 7.20 (m,10H), 7.50 (br d, 2H), 7.70 (m, 2H), 8.00 (br d, 2H). Mass spectrum:(M+H)⁺ =817.

Example 306 (2S,5S)-Bis-(N-((6-methyl-2-pyridinyl)methoxycarbonyl)valinyl)amino)-1,6-diphenyl-3,3-difluoro-4-oxo-hexane

Oxidation of the resultant compound from Example 305 using sodiumdichromate in acetic acid provided the desired compound in 69% yield. ¹H NMR (DMSO-d₆ ; 300 MHz): 0.68 (d, 3H), 0.74 (d, 3H), 0.80 (d, 6H),1.80 (m, 1H), 1.90 (m, 1H), 2.46 (s, 3H), 2.47 (s, 3H), 3.80-3.90 (m,2H), 5.03 (s, 4H), 7.15 (m, 14H), 7.30 (br d, 1H), 7.67 (t, 2H), 8.25(br d, 1H), 8.62 (br d, 1H). Mass spectrum: (M+H)⁺ =815.

Example 307 (2S, 3S,5S)-2-(N-((5-Methyl-2-pyrazinyl)methoxycarbonyl)valinyl)amino)5-(N-(3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Coupling of ((5-methyl-2-pyrazinyl)methoxycarbonyl)valine with (2S, 3S,5S)-2-amino-5-(N((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneusing standard EDAC/HOBt method provided the desired compound in 80%yield. ¹ H NMR (DMSO-d₆ ; 300 MHz): 0.72 (d, 3H), 0.77 (d, 3H), 1.50 (m,2H), 1.85 (m, 1H), 2.48 (s, 3H), 2.60-270 (m, 4H), 3.80 (m, 2H), 4.10(m, 1H), 4.88 (br d, 1H), 4.92 (m, 2H), 5.10 (s, 2H), 7.10-7.30 (m,14H), 7.45 (br d, 1H), 7.50 (br d, 1H), 8.50 (m, 4H). Mass spectrum:(M+H)⁺ =669.

Example 308 (2S, 3S, 5S)-2-(N((3-Pyridinyl)methoxycarbonyl)amino)-5-(N((5-methyl-2-pyrazinyl)methoxycarbonyl)valinyl)amino)-1,6-diphenyl-3-hydroxyhexane

Coupling of ((5-methyl-2-pyrazinyl)methoxycarbonyl)valine with (2S, 3S,5S)-2-(N-((3-pyridinyl)methoxycarbonyl)amino)-5-amino-1,6-diphenyl-3-hydroxyhexaneusing standard EDAC/HOBt method provided the desired compound in 80%yield. ¹ H NMR (DMSO-d₆ ; 300 MHz): 0.70 (d, 3H), 0.73 (d, 3H), 1.40 (m,2H), 1.80 (m, 1H), 2.45 (s, 3H), 2.60 (m, 4H), 3.70 (m, 2H), 4.05 (m,1H), 4.60 (d, 1H), 4.90 (m, 2H), 5.08 (s, 2H), 6.85 (br d, H), 7.05-7.30(m, 12H), 7.50 (br d, 1H), 7.70 (br d, 1H), 8.45 (m, 4H). Mass spectrum:(M+H)⁺ =669.

Example 309 (2S, 3S,5S)-2-(N-(6-Methoxy-3-pyridinyl)methoxycarbonyl)valinyl)amino)5-(N-(3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Coupling of ((6-methoxy-3-pyridinyl)methoxycarbonyl)valine with (2S, 3S,5S)-2-amino-5(N((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneusing standard EDAC/HOBt method provided the desired compound in 90%yield. ¹ H NMR (DMSO-d₆ ; 300 MHz): 0.70 (d, 3H), 0.73 (d, 3H), 1.50 (m,2H), 1.85 (m, 1H), 2.65 (m, 4H), 3.82 (s, 3H), 4.90-4.96 (m, 5H), 6.80(m, 1H), 7.10-7.20 (m, 12H), 7.30 (m, 1H), 7.40 (m, 1H), 7.50 (m, 1H),7.65 (m, 1H), 8.18 (m, 1H), 8.46 (m, 2H). Mass spectrum: (M+H)⁺ =684.

Example 310 (2S,3S,5S)-2-[N((3-pyridinyl)methoxycarbonyl]amino)-5-(N((6-methoxy-3-pyridinyl)methoxycarbonyl)valinyl)amino)-1,6-diphenyl-3-hydroxyhexane

Coupling of ((5-methoxy-3-pyridinyl)methoxycarbonyl)valine with (2S, 3S,5S)-2-(N-((3-pyridinyl)methoxycarbonyl)amino)-5-amino-1,6-diphenyl-3-hydroxyhexaneusing standard EDAC/HOBt method provided the desired compound in 79%yield. ¹ H NMR (DMSO-d₆ ; 300 MHz): δ0.73 (m, 6H), 1.45 (m, 2H), 1.80(m, 1H), 2.60-2.70 (m, 4H), 3.83 (s, 3H), 4.10 (m, 1H), 4.62 (m, 1H),4.97 (m, 4H), 6.80 (br d, 1H), 6.90 (br d, 1H), 7.00-7.35 (m, 12H), 7.57(br d, 1H), 7.70 (m, 2H), 8.18 (m, 1H), 8.50 (m, 2H). Mass spectrum:(M+H)⁺ =684.

Example 311 (2S,3S,5S)-2-(N-(N-((N-Methyl-N-((6-methoxy-3-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Coupling of(N-((N-methyl-N-((6-methoxy-3-pyridinyl)methyl)amino)carbonyl)valinewith (2S, 3S,5S)-2-amino-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneusing standard EDAC/HOBt method provided the desired compound in 83%yield. ¹ H NMR (DMSO-d₆ ; 300 MHz): δ0.71 (d, 3H), 0.77 (d, 3H), 1.5 (m,2H), 1.95 (m, 1H), 2.65-2.73 (m, 4H), 2.77 (s, 3H), 3.80 (s, 3H), 3.93(m, 1H), 4.15 (m, 1H), 4.38 (m, 2H), 4.86 (br d, 1H), 4.93 (m, 2H), 6.00(br d, 1H), 6.77 (d, 1H), 7.05-7.20 (m, 10H), 7.36 (m, 1H), 7.48 (br d,1H), 7.55 (m, 1H), 8.03 (d, 1H), 8.50 (m, 2H). Mass spectrum: (M+H)⁺=697.

Example 312 (2S, 3S,5S)-2-(N-((3-Pyridinyl)methoxycarbonyl)amino-5-(N-(N-((N-methyl-N-((6-methoxy-3-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-1,6-diphenyl-3-hydroxyhexane

Coupling of(N-((N-methyl-N-((6-methoxy-3-pyridinyl)methyl)amino)carbonyl)valinewith(2S,3S,5S)-2-(N-((3-pyridinyl)methoxycarbonyl)amino)-5-amino-1,6-diphenyl-3-hydroxyhexaneusing standard EDAC/HOBt method provided the desired compound in 90%yield. ¹ H NMR (DMSO-d₆ ; 300 MHz): δ0.73 (d, 3H), 0.76 (d, 3H), 1.48(m, 2H), 1.90 (m, 1H), 2.60-2.70 (m, 4H), 2.77 (s, 3H), 3.60 (m, 1H),3.81 (s, 3H), 3.90 (m, 1H), 4.13 (m, 1H), 4.38 (m, 2H), 4.62 (d, 1H),4.95 (m, 2H), 5.80 (br d, 1H), 6.75 (d, 1H), 6.88 (br d, 1H), 7.07-7.21(m, 10H), 7.32 (m, 1H), 7.55 (m, 2H), 7.70 (br d, 1H), 8.03 (d, 1H),8.50 (m, 2H). Mass spectrum: (M+H)⁺ =697.

Example 313 (2S, 3S,5S)-2-(N-(N-((N-Methyl-N-((5-methyl-3-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Coupling of(N-((N-methyl-N-((5-methyl-3-pyridinyl)methyl)amino)carbonyl)valine with(2S, 3S,5S)-2-amino-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneusing standard EDAC/HOBt method provided the desired compound in 82%yield. ¹ H NMR (DMSO-d₆ ; 300 MHz): 0.72 (d, 3H), 0.77 (d, 3H), 1.50 (m,2H), 1.90 (m, 1H), 2.25 (s, 3H), 2.60-276 (m, 4H), 2.80 (s, 3H), 3.55(m, 1H), 3.85-4.10 (m, 3H), 4.45 (m, 2H), 4.86 (d, 1H), 4.93 (m, 2H),6.02 (d, 1H), 7.10-7.20 (m, 11H), 7.35 (m, 1H), 7.42 (m, 1H), 7.50 (m,2H), 8.27 (m, 2H), 8.50 (m, 2H). Mass spectrum: (M+H)⁺ =681.

Example 314(2S,3S,5S)-2-(N-((3-pyridinyl)methoxycarbonyl)amino-5-(N-(N-((N-methyl-N-((5-methyl-3-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-1,6-diphenyl-3-hydroxyhexane

Coupling of(N-((N-methyl-N-((5-methyl-3-pyridinyl)methyl)amino)carbonyl)valine with(2S, 3S,5S)-2-(N-((3-pyridinyl)methoxycarbonyl)amino)-5-amino-1,6-diphenyl-3-hydroxyhexaneusing standard EDAC/HOBt method provided the desired compound in 80%yield. ¹ H NMR (DMSO-d₆ ; 300 MHz): δ0.72 (d, 3H), 0.75 (d, 3H), 1.4 5(m, 2H), 1.88 (m, 1H), 2.24 (s, 3H), 2.55-2.70 (m, 4H), 2.80 (s, 3H),3.57 (m, 1H), 3.80 (m, 1H), 3.90 (m, 1H), 4.10 (m, 1H), 4.45 (s, 2H),4.68 (d, 1H), 4.96 (m, 2H), 5.96 (br d, 1H), 6.92 (br d, 1H), 7.10-7.20(m, 11H), 7.30 (m, 1H), 7.42 (m, 1H), 7.55 (m, 1H), 7.70 (br d, 1H),8.28 (m, 2H), 8.50 (m, 2H). Mass spectrum: (M+H)⁺ =681.

Example 315(2S,5S)-Bis-(N-((6-Methoxy-3-pyridinyl)methoxycarbonyl)valinyl)amino)-1,6-diphenyl-3(S)-hydroxyhexane

Coupling of ((6-methoxy-3-pyridinyl)methoxycarbonyl)valine with (2S, 3S,5S)-2,5-diamino-1,6-diphenyl-3-hydroxyhexane using standard EDAC/HOBtmethod provided the desired product in 60% yield. ¹ H NMR (DMSO-d₆ ; 300MHz): δ0.70 (d, 6H), 1.45 (m, 2H), 1.80 (m, 2H), 2.60-2.70 (m, 4H), 3.82(s, 6H), 4.05 (m, 2H), 4.90 (d, 2H), 4.98 (4H), 6.82 (d, 2H), 7.00-7.20(m, 14H), 7.45 (br d, 1H), 7.70 (m, 3H), 8.20 (m, 2H). Mass spectrum:(M+H)⁺ =813.

Example 316(2S,3S,5S)-2-(N-((2-pyrazinyl)methoxycarbonyl)valinyl)amino)-5-(N-(3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Coupling of N-((2-piprazinyl)methoxycarbonyl)valine with(2S,3S,5S)-2-amino-5-(N-(3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneprovided the desired compound in 95% yield. ¹ H NMR (DMSO-d₆ ; 300 MHz):δ0.73 (d, 3H), 0.80 (d, 3H), 1.50 (m, 2H), 1.90 (m, 1H), 2.60-2.70 (m,4H), 3.56 (m, 1H), 3.80 (m, 2H), 4.10 (m, 1H), 4.90 (m, 3H), 5.15 (s,2H), 7.10-7.20 (m, 12H), 7.35 (m, 2H), 7.50 (m, 2H), 8.50-8.70 (m, 5H).Mass spectrum: (M+H)⁺ =655.

Example 317(2S,3S,5S)-2-(N-((3-pyridinyl)methoxycarbonyl)amino)-5-(N((2-pyrazinyl)methoxycarbonyl)valinyl)amino)-1,6-diphenyl-3-hydroxyhexane

Coupling of N-((2-pyrazinyl)methoxycarbonyl)valine with(2S,3S,5S)-2-(N-((3-pyridinyl)methoxycarbonyl)amino-5-amino-1,6-diphenyl-3-hydroxyhexaneusing standard EDAC/HOBt method provided the desired compound in 60%yield. ¹ H NMR (DMSO-d₆ ; 300 MHz): δ0.77 (t, 6H), 1.4 6 (m, 2H), 1.85(m, 1H), 2.60-2.70 (m, 4H), 3.58 (m, 1H), 3.77 (m, 2H), 4.12 (m, 1H),4.64 (d, 1H), 4.96 (m, 2H), 5.17 (s, 2H), 6.90 (br d, 1H), 7.10-7.30 (m,14H), 7.55 (m, 1H), 7.70 (br d, 1H), 8.50 (m, 2H), 8.60 (m, 2H), 8.68(s, 1H). Mass spectrum: (M+H)⁺ =655.

Example 318

A. (2S, 3S,5S)-5-Amino-2-(N-((5-pyrimidinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneand(2S,3S,5S)-2-Amino-5-(N-((5-pyrimidinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 37B but replacing the resultant compoundof Example 37A with the resultant compound of Example 167A provided 68.1mg (13%) of (2S, 3S,5S)-5-amino-2-(N-((5-pyrimidinyl)methoxycarbonyl)-amino)-1,6-diphenyl-3-hydroxyhexaneand 148.1 mg (28%) of (2S, 3S,5S)-2-amino-5-(N-((5-pyrimidinyl)methoxycarbonyl)-amino)-1,6-diphenyl-3-hydroxyhexane

B. (2S, 3S,5S)-2-(N-(N-((N-Methyl-N-((2-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-5-(N-((5-pyrimidinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

A mixture of 50 mg (0.119 mmol) of(2S,3S,5S)-2-amino-5-(N-((5-pyrimidinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneand 68.9 mg (0.178 mmol) of the resultant compound of Example 3F in 1 mlof tetrahydrofuran was stirred at ambient temperature for 16 h. Thesolvent was then removed in vacuo, and the residue was purified bysilica gel chromatography using 5% methanol in dichloromethane provided63.5 mg (80%) of the desired compound as a white solid. ¹ H NMR (CDCl₃)δ0.78 (d, 3H), 0.92 (d, 3H), 1.65 (m, 2H), 2.26 (m, 1H), 2.74 (m, 2H),2.83 (m, 2H), 2.97 (s, 3H), 3.63 (m, 1H), 3.95 (m, 1H), 4,05 (m, 2H),4.45 (s, 2H), 5.02 (dd, 2H), 5.33 (br d, 1H), 6.48 (br d, 1H), 6.56 (br,1H), 7.07-7.24 (m, 12H), 7.72 (td, 1H), 8.51 (d, 1H), 8.67 (s, 2H), 9.18(s, 1H). Mass spectrum: (M+H)⁺ =668.

Example 319(2S,3S,5S)-2-(N-(N-((2-Pyridinyl)methoxycarbonyl)valinyl)amino)-5-(N-((5-pyrimidinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 318B but replacing the resultant compoundof Example 3F with the resultant compound of Example 2D provided 48.9 mg(63%) of the desired compound as a white solid. ¹ H NMR (CDCl₃) δ0.76(d, 3H), 0.89 (d, 3H), 1.64 (m, 2H), 2.13 (m, 1H), 2.75 (d, 2H), 2.85(d, 2H), 3.68 (m, 1H), 3.93 (m, 2H), 4.08 (m, -1H), 4.96-5.33 (m, 6H),6.34 (br, 1H), 7.04-7.22 (m, 11H), 7.33 (d, 1H), 7.70 (td, 1H), 8.57 (d,1H), 8.68 (s, 2H), 9.18 (s, 1H). Mass spectrum: (M+H)⁺ =655.

Example 320 (2S,3S,5S)-5-(N-(N-((N-Methyl-N-((2-pyridinyl)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5-pyrimidinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 318B but replacing (2S, 3S,5S)-2-amino-5-(N-((5-pyrimidinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith (2S, 3S,5S)-5-amino-2-(N-((5-pyrimidinyl)methoxycarbonyl)-amino)-1,6-diphenyl-3-hydroxyhexaneprovided 60.4 mg (76%) of the desired compound as a white solid. ¹ H NMR(CDCl₃) δ0.77 (d, 3H), 0.90 (d, 3H), 1.62 (m, 2H), 2.31 (m, 1H), 2.73(m, 2H), 2.84 (m, 2H), 2.99 (s, 3H), 3.66 (m, 1H), 3.74 (m, 1H), 4.04(m, 1H), 4.22 (m, 1H), 4.43 (dd, 2H), 5.03 (dd, 2H), 5.24 (br d, 1H),6.52 (br d, 1H), 6.66 (br, 1H), 7.08-7.28 (m, 12H), 7.74 (td, 1H), 8.49(dd, 1H), 8.67 (S, 2H), 9.18 (S, 1H). Mass spectrum: (M+H)⁺ =668.

Example 321 (2S,3S,5S)-5-(N-(N-((2-Pyridinyl)methoxycarbonyl)valinyl)amino)-2-(N-((5-pyrimidinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 318B but replacing(2S,3S,5S)-2-amino-5-(N-((5-pyrimidinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith (2S, 3S,5S)-5-amino-2-(N-((5-pyrimidinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneand replacing the resultant compound of Example 3F with the resultantcompound of Example 2D provided 14.6 mg (78%) of the desired compound asa white foamy solid. ¹ H NMR (CDCl₃) δ0.71 (d, 3H), 0.86 (d, 3H), 1.67(m, 2H), 2.07 (m, 1H), 2.30 (m, 4H), 3.68 (m, 1H), 3.77 (m, 1H), 3.90(m, 1H), 4.26 (m, 1H), 5.03 (dd, 2H), 5.19 (dd, 2H), 5.22 (br, 1H), 6.45(br, 1H), 7.09-7.23 (m, 12H), 7.34 (d, 1H), 7.73 (td, 1H), 8.57 (dd,1H), 8.67 (s, 2H), 9.18 (s, 1H). Mass spectrum: (M+H)⁺ =655.

Example 322

A.(2S,3S,5S)-5-Amino-2-(N-((3-furyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneand (2S, 3S,5S)-2-Amino-5-(N-((3-furyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 37B but replacing the resultant compoundof Example 37A with 3-furylmethyl 4-nitrophenyl carbonate from Example273 provided 69.0 mg (17%) of (2S, 3S,5S)-5-amino-2-(N-((3-furyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneand 156.4 mg (36%) of (2S, 3S,5S)-2-amino-5-(N-((3-furyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

B. (2S, 3S,5S)-2-(N-(N-(2-(6-Methylpyridinyl)methoxycarbonyl)valinyl)amino)-5-(N-((3-furyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 6I but replacing the resultant compoundof Example 6H with(2S,3S,5S)-2-amino-5-(N-((3-furyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneand replacing trans-3-(pyridinyl)acrylic acid with the resultantcompound of Example 288 provided 92.9 mg (96%) of the desired compoundas a white solid. ¹ H NMR (CDCl₃) δ0.73 (d, 3H), 0.87 (d, 3H), 1.64 (m,2H), 2.13 (m, 1H), 2.50 (s, 3H), 2.76 (dd, 2H), 2.84 (d, 2H), 3.67 (m,1H), 3.75 (m, 1H), 3.88 (m, 1H), 4.17 (m, 1H), 4.90 (s, 2H), 5.09 (br d,1H), 5.15-5.22 (m, 3H), 6.31 (br d, 1H), 6.37 (s, 1H), 7.07-7.25 (m,12H), 7.39 (m, 2H), 7.60 (t, 1H). Mass spectrum: (M+H)⁺ =657.

Example 323 A. Methyl 3-(Methoxymethoxy)-5-isoxazole Carboxylate

A solution of 2.0 g (14.0 mmol) of methyl 3-hydroxy-5-isoxazolecarboxylate and 29.2 ml (16.8 mmol) of N,N-diisopropylethylamino in 20ml of tetrahydrofuran was treated with 1.27 ml of chloromethyl methylether. After being stirred at ambient temperature for 2 h, the solutionwas diluted with dichloromethane, washed with water, dried over MgSO₄,and concentrated in vacuo. Silica gel chromatography of the residueusing 10% methanol in dichloromethane provided 129.6 mg (78%) of thedesired compound as a white solid. ¹ H NMR (CDCl₃) δ3.57 (s, 3H), 3.96(s, 3H), 5.37 (s, 2H), 6.64 (s, 1H).

B. 5-(Hydroxymethyl)-3-(methoxymethoxy)isoxazole

A suspension of 0.40 g (10.7 mmol) of lithium aluminum hydride in 40 mlof tetrahydrofuran was treated with 2.0 g of the resultant compound ofExample 323A in 40 ml of tetrahydrofuran. After being stirred at ambienttemperature for 5 h, the solution was treated with 20 ml of saturatedammonium chloride solution, extracted with three 20 ml portions ofdichloromethane. The combined organic layers were dried over MgSO₄, andconcentrated in vacuo provided 1.25 g of the desired compound as ayellow oil. ¹ H NMR (CDCl₃) δ3.55 (s, 3H), 4.66 (s, 2H), 5.31 (s, 2H),5.97 (s, 1H). Mass spectrum: (M+H)⁺ =160.

C. p-Nitrophenyl (5-(3-(Methoxymethoxy)isoxazolyl)methoxy)formate

Using the procedure of Example 37A but replacing3-(hydroxymethyl)pyridine with the resultant compound of Example 323Bprovided 2.14 g (84%) of the desired compound as a pale yellow solid. ¹H NMR (CDCl₃) δ3.57 (s, 3H), 5.28 (s, 2H), 5.35 (s, 2H), 6.17 (s, 1H),7.42 (dr, 2H), 8.30 (dr, 2H). Mass spectrum: (M+H)⁺ =325.

D. (2S,3S,5S)-2,5-Bis-(N-(5-(3-(methoxymethoxy)isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

A mixture of 50 mg (0.176 mmol) of the resultant compound of Example 1Eand 171.0 mg (0.527 mmol) of the resultant compound of Example 323C in 2ml of tetrahydrofuran was stirred at ambient temperature for 20 h. Thesolvent was then removed in vacuo, and the residue was purified bysilica gel chromatography using 5% methanol in dichloromethane provided78.2 mg (69%) of the desired compound as a white solid. ¹ H NMR (CDCl₃)δ1.64 (m, 2H), 2.76 (d, 2H), 2.85 (d, 2H), 3.54 (s, 6H), 3.66 (m, 1H),3.81 (m, 1H), 3.96 (m, 1H), 4.95 (br, 2H), 4.99 (s, 4H), 5.19 (br d,1H),5.30 (s, 4H), 5.91 (d, 2H), 7.07-7.30 (m, 10H). Mass spectrum:(M+H)⁺ =655.

Example 324 A. 4-(Hydroxymethyl)isoxazole

0.50 g (2.57 mmol) of 3,3-dimethoxy-2-(dimethoxymethyl)-1-propanol wasadded dropwise to a solution of 0.18 g (2.57 mmol) of hydroxyaminehydrochloride in 2 ml of water and 0.2 ml of 1N aqueous HCl. The mixturewas then refluxed for 1 h. After cooling, the resulting solution wasneutralized with solid NaHCO₃, extracted with five 5 ml portions ofdichloromethane. The combined organic layers were dried over MgSO₄, andconcentrated in vacuo provided 1.25 g of the desired compound as ayellow oil. ¹ H NMR (CDCl₃) δ4.67 (s, 2H), 8.33 (s, 1H), 8.42 (s, 1H).

B. p-Nitrophenyl (4-Isoxazolyl)methoxy)formate

Using the procedure of Example 37A but replacing3-(hydroxymethyl)pyridine with the resultant compound of Example 324Aprovided 134.0 mg (39%) of the desired compound as a pale yellow solid.¹ H NMR (CDCl₃) δ5.23 (s, 2H), 7.39 (dt, 2H), 8.29 (dr, 2H), 8.44 (s,1H), 8.63 (s, 1H).

C. (2S, 3S,5S)-2,5-Bis-(N-(4-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

A mixture of 50 mg (0.176 mmol) of the resultant compound of Example 1Eand 116.0 mg (0.440 mmol) of the resultant compound of Example 324B in 1ml of tetrahydrofuran was stirred at ambient temperature for 20 h. Thesolvent was then removed in vacuo, and the residue was purified bysilica gel chromatography using 5% methanol in dichloromethane provided68.0 mg (72%) of the desired compound as a white solid. ¹ H NMR (CDCl₃)δ1.61 (m, 2H), 2.74 (d, 2H), 2.83 (d, 2H), 3.65 (m, 1H), 3.79 (m, 1H),3.94 (m, 1H), 4.73 (br, 1H), 4.94 (dd, 4H), 4.98 (br, 1H), 7.05-7.25 (m,10H), 8.26 (two s, 2H), 8.40 (two s, 2H). Mass spectrum: (M+H)⁺ =535.

Example 325 (2S,3S,5S)-2,5-Bis-(N-((3-pyridazinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneA. Phenyl ((3-Pyridazinyl)methoxy)formate

Using the procedure of Example 176 but replacing2-(hydroxymethyl)pyridine with 3-(hydroxymethyl)pyridazine provided252.0 mg (60%) of the desired compound as a white solid. ¹ H NMR (CDCl₃)δ5.63 (s, 2H), 7.20-7.29 (m, 3H), 7.37-7.44 (m, 2H), 7.56 (dd, 1H), 9.21(dd, 1H). Mass spectrum: (M+H)⁺ =231.

B. (2S, 3S,5S)-2,5-Bis-(N-((3-pyridazinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

A mixture of 50 mg (0.176 mmol) of the resultant compound of Example 1Eand 122.0 mg (0.527 mmol) of the resultant compound of Example 325A in 1ml of dimethylformamide was stirred at 50° C. for 2 days. The solventwas then removed in vacuo, and the residue was purified by silica gelchromatography using 5% methanol in dichloromethane provided 48.2 mg(49%) of the desired compound as a white solid. ¹ H NMR (CDCl₃) δ1.73(m, 2H), 2.79 (d, 2H), 2.91 (d, 2H), 3.78 (br, 1H), 3.89 (dd, 1H), 4.04(br, 1H), 5.33 (dd, 2H), 5.36 (dd, 2H), 5.49 (br, 1H), 5.64 (br d, 1H),7.11-7.34 (m, 12H), 7.43 (m, 2H), 9.11 (d, 2H).

Example 326 A. 2-(Hydroxymethyl)quinoline

A solution of 3.0 g of quinoline-2-carboxaldehyde in 100 ml of ethanolwas treated with 750 mg of sodium borohydride and stirred at ambienttemperature for 15 min. The resulting solution was neutralized with 1NHCl, concentrated in vacuo, and extracted three times with ethylacetate. The combined organic layers were dried over Na₂ SO₄ andconcentrated to provide 2.65 g (88%) of the crude desired compound.

B. N-((2-Quinolinyl)methoxycarbonyl)valine Methyl Ester

Using the procedure of Example 2B but replacing pyridine-2-methanol withthe resultant compound of Example 326A provided the desired compound(R_(f) 0.55, 50% ethyl acetate in hexane) in 85% yield.

C. N-((2-Quinolinyl)methoxycarbonyl)valine

Using the procedure of Example 3E but replacing the resultant compoundof Example 3D with the resultant compound of Example 326B provided thedesired compound.

D.(2S,3S,5S)-2-(N-(N-((2-Quinolinyl)methoxycarbonyl)valinyl)amino)-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 81C but replacing the resultant compoundof Example 81B with the resultant compound of Example 326C and replacingthe resultant compound of Example 62A with(2S,3S,5S)-2-amino-5-(N-((3-pyridinyl)methoxycarbonyl)-amino)-1,6-diphenyl-3-hydroxyhexaneprovided, after silica gel chromatography using a gradient of 2-4%methanol in chloroform, 105 mg (60%) of the desired compound (R_(f)0.63, 10% methanol in chloroform) as a white solid, m.p. 159°-163° C.Mass spectrum: (M+1)⁺ =704.

Example 327(2S,3S,5S)-5-(N-(N-((2-Quinolinyl)methoxycarbonyl)valinyl)amino)-2-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 81C but replacing the resultant compoundof Example 81B with the resultant compound of Example 326C and replacingthe resultant compound of Example 62A with (2S,3S,5S)-5-amino-2-(N-((3-pyridinyl)methoxycarbonyl)-amino)-1,6-diphenyl-3-hydroxyhexaneprovided, after silica gel chromatography using a gradient of 2-4%methanol in chloroform, 101 mg (59%) of the desired compound (R_(f)0.61, 10% methanol in chloroform) as a while solid, m.p. 141°-143° C.Mass spectrum: (M+1)⁺ =704.

Example 328 A.(1S,2S)-2-((3-Pyridinyl)methoxycarbonyl)amino-1-cyclopentanol

Using the procedure of Example 42A but replacing(S,S)-2-aminocyclohexanol with (S,S)-2-aminocyclopentanol (Overman andSugai, et. al., J. Org. Chem. 1985, 50, 4154), provided, after silicagel chromatography using first 20% ethyl acetate in chloroform then 5%methanol in chloroform, 324 mg (66%) of the desired compound (R_(f)0.33, 10% methanol in chloroform). ¹ H NMR (CDCl₃) δ1.40 (dq, J=12, 8Hz, 1H), 1.6-1.9 (m, 3H), 2.02 (m, 1H), 2.15 (m, 1H), 3.70 (m,. 1H),4.01 (br q, 1H), 4.91 (br, 1H), 5.13 (s, 2H), 7.30 (dd, J=7, 5 Hz, 1H),7.71 (d, J=8 Hz, 1H), 8.59 (dd, J=5, 1 Hz, 1H), 8.62 (br s, 1H). Massspectrum: (M+1)⁺ =237.

B.(1'S,2'S)-(2-((3-pyridinyl)methoxycarbonyl)amino-1-cyclopentyl)-4-nitrophenylcarbonate

Using the procedure of Example 42B but replacing the resultant compoundof Example 42A with the resultant compound of Example 328A, provided,after silica gel chromatography using first 20% ethyl acetate inchloroform then 4% methanol in chloroform, 495 mg (90%) of the desiredcompound (R_(f) 0.63, 10% methanol in chloroform). ¹ H NMR (CDCl₃)δ1.5-1.6 (m, 1H), 1.75-1.95 (m, 3H), 2.1-2.3 (m, 2H), 4.13 (m, 1H), 4.98(br, 1H), 5.04 (m, 1H), 5.14 (s, 2H), 7.29 (dd, J=7, 5 Hz, 1H), 7.38 (d,J=10 Hz, 2H), 7.70 (d, J=8 Hz, 1H), 8.27 (d, J=10 Hz, 2H), 8.58 (br d,1H), 8.63 (br s, 1H). Mass spectrum: (M+H)⁺ =402.

C. (2S,3S, 5S,1'S,2'S,1"S,2"S)-2,5-Bis-(N-(2-(N-((3-pyridinyl)methoxycarbonyl)amino-1-cyclopentyl)oxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 42C but replacing the resultant compoundof Example 42B with the resultant compound of Example 328B, provided,after filtration, the desired compound (R_(f) 0.27, 10% methanol inchloroform) in 65% yield, m.p. 190°-192° C. Mass spectrum: (M+1)⁺ =809.

Example 329

(2S, 3S, 5S, 1'S,2'S)-2-(N-(2-(N-((3-Pyridinyl)methoxycarbonyl)amino-1-cyclopentyl)oxycarbonyl)amino)-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

A solution of 25 mg (0.06 mmol) of the resultant compound of Example328B and 26 mg (0.06 mmol) of(2S,3S,5S)-2-amino-5-(N-((3-pyridinyl)methoxycarbonyl)-amino)-1,6-diphenyl-3-hydroxyhexanein 5 ml of tetrahydrofuran was stirred for 16 h at ambient temperature.The resulting solution was concentrated in vacuo and purified by silicagel chromatography using first 20% ethyl acetate in chloroform then 4%methanol in chloroform to provide 35 mg (86%) of the desired compound(R_(f) 0.21, 10% methanol in chloroform) as a white solid, m.p. 98°-100°C. Mass spectrum: (M+1)⁺ =682.

Example 330

(2S,3S, 5S,1'S,2'S)-5-(N-2-(N-((3-Pyridinyl)methoxycarbonyl))amino-1-cyclopentyl)oxycarbonyl)amino)-2-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

Using the procedure of Example 329 but replacing (2S,3S,5S)-2-amino-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexanewith (2S, 3S,5S)-5-amino-2-(N-((3-pyridinyl)methoxycarbonyl)-amino)-1,6-diphenyl-3-hydroxyhexaneprovided, after silica gel chromatography using a gradient of first 20%ethyl acetate in chloroform then 4% methanol in chloroform, 35 mg (85%)of the desired compound (R_(f) 0.22, 10% methanol in chloroform) as awhite solid, m.p. 125°-128° C. Mass spectrum: (M+1)⁺ =682.

Example 331 (2S,3S,5S)-2,5-Bis-(N-((3-methyloxetan-3-yl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneExample 331A 3-phenyloxycarbonyloxymethyl-3-methyloxetane

A 0.552 mL (4.42 mmol) sample of phenoxycarbonylchloride in 2 mL ofmethylene chloride was added to a solution of 376 mg (3.68 mmol) of3-hydroxymethyl-3-methyloxetane and 60.7 mL (5.52 mmol) of4-methylmorpholine in 2 mL of methylene chloride cooled in an ice bath.The mixture was stirred at 0° C. for 3.5 hours. The mixture was dilutedwith methylene chloride, which was washed with water, dried andconcentrated. The crude product was chromatographed on silica gel,eluting with 20% ethyl acetate in hexane. The solvent was removed andthe product dried to afford 0.582 g of the title compound, which wastaken directly to the next step.

Example 331B(2S,3S,5S)-2,5-Bis-(N-((3-methyloxetan-3-yl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

A 180 mg sample of the compound from Example 331A above was added to 57mg (0.203 mmol) of the product of Example 1E and then dissolved in DMFand heated at 50° C. overnight. The solvent was removed and the crudeproduct chromatographed on silica gel, eluting with 2% methanol inchloroform. The solvent was removed and the product dried to afford 52.9mg of the title compound. MS M/Z (DCI/NH₃): 541 (M+H), 558 (M+18). Anal.calc. for C₃₀ H₄₀ N₂ O₇.0.5 H₂ O: C, 65.57; H, 7.47; N, 5.10; found: C,65.80; H, 7.41; N, 5.19. Proton NMR (DMSO): δ1.18 (m, 6H), 1.51 ((t,2H), 2.58-2.73 (4H), 3.58 (m, 1H), 3.84 (m, 2H), 3.95 (m, 4H), 4.15 (m,4H), 4.30 (m, 4H), 4.67 (d, 1H), 6.78 (d, 1H), 7.05 (d, 1H), 7.11-7.27(10H).

Example 332 (2S, 3S,5S)-2,5-Bis-(N-((2,3-dihydrofuro[2,3-b]pyridin-3-yl)oxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneExample 332A 3-p-Nitrophenoxycarbonyloxy-2,3-dihydrofuro[2.3-b]pyridine

A 534 mg (2.65 mmol) sample of p-nitrophenoxycarbonylchloride inmethylene chloride was added to a solution of 330 mg (2.41 mmol) of3-hydroxy-2,3-dihydrofuro[2,3-b]pyridine (prepared as described by H.Sliwa, Bull. Soc. Chim. Fr. 1970 (2), 646-652) and 0.291 mL of4-methylmorpholine in 2 mL of methylene chloride cooled in an ice bath.The mixture was stirred at 0° C. for 2.75 hours. The mixture was dilutedwith methylene chloride, which was washed with water, dried andconcentrated. The crude product was chromatographed on silica gel,eluting with 5% ethyl acetate in methylene chloride. The solvent wasremoved and the product dried to afford 0.493 g of the title compound,which was taken directly to the next step.

Example 332B (2S,3S,5S)-2,5-Bis-(N-((2,3-dihydrofuro[2,3-b]pyridin-3-yl)oxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

A 164 mg (0,544 mmol) sample of the compound from Example 332A above wasadded to 51.5 mg (0.181 mmol) of the product of Example 1E in 0.5 mL ofDMF and stirred for 7 hours. The solvent was removed and the crudeproduct chromatographed on silica gel, eluting with 2% and 5% methanolin chloroform. The solvent was removed and the product dried to afford62.8 mg of the title compound. MS M/Z (FAB): 611 (M+H). Anal. calc. forC₃₄ H₃₄ N₄ O₇.2H₂ O: C, 63.15; H, 5.88; N, 9.18; found: C, 63.22; H,5.41; N, 8.64. Proton NMR (DMSO): δ1.50 (m, 2H), 2.50-2.75 (4H), 3.92(bs, 2H), 4.18 (m, 1H), 4.36 (m, 1H), 4.58 (m, 2H), 4.68 (m, 2H), 6.0(m, 2H), 6.94 (m, 3H), 7.1-7.3 (11H), 7.59 (m, 1H) 7.83 (d, 1H), 8.12(m, 2H).

Example 333 (2S, 3S, 5S,1'S)-2,5-Bis-(N-(1-(3-pyridyl)ethoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneExample 333A (S)-3-(1-(p-Nitrophenoxycarbonyloxy)ethyl)pyridine

A 534 mg (2.65 mmol) sample of p-nitrophenoxycarbonylchloride inmethylene chloride was added to a solution of 74 mg (0.606 mmol) of(S)-1-(3-pyridyl)ethanol and 0.080 mL of 4-methylmorpholine in 2 mL ofmethylene chloride cooled in an ice bath. The mixture was stirred at 0°C. for 3.5 hours. The mixture was diluted with methylene chloride, whichwas washed with water, dried and concentrated. The crude product waschromatographed on silica gel, eluting with 50% and 90% ethyl acetate inhexane. The solvent was removed and the product dried to afford 0.078 gof the title compound, which was taken directly to the next step.

Example 333B (2S, 3S, 5S,1'S)-2,5-Bis-(N-(1-(3-pyridyl)ethoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

A 68 mg (0.236 mmol) sample of the compound from Example 333A above wasadded to 22 mg (0.079 mmol) of the product from Example 1E in 1.0 mL ofDMF and stirred for 16 hours. The solvent was removed and the crudeproduct chromatographed on silica gel, eluting with 2%,5% and 10%methanol in methylene chloride. The solvent was removed and the productdried to afford 25.0 mg of the title compound. MS M/Z (DCI/NH₃): 583(M+H). Proton NMR (DMSO): δ1.02-1.16 (1H), 1.43 (m, 6H), 1.54 (m, 2H),2.58-2.70 (m, 4H), 3.45 (m, 1H), 3.60 (m, 1H), 3.75-3.90 (2H), 4.70 (d,1H), 5.62 (m, 2H), 6.93 (d, 1H), 7.09 (d, 2H), 7.14-7.22 (9H), 7.30 (m,1H), 7.53 (m, 1H), 8.47 (br, 4H).

Example 334(2S,3S,5S)-2,5-Bis-(N-(isoxazol-5-ylmethoxycarbonyl)amino)-1.6-diphenyl-3-hydroxyhexaneExample 334A 5-(p-Nitrophenoxycarbonyloxymethyl)isoxazole

A 631 mg (2.65 mmol) sample of p-nitrophenoxycarbonylchloride in 2 mL ofmethylene chloride was added to a solution of 310 mg (3.13 mmol) of5-hydroxymethyisoxazole and 0.344 mL of 4-methylmorpholine in 2 mL ofmethylene chloride cooled in an ice bath. The solution was stirred for 4hours. The mixture was diluted with methylene chloride, which was washedwith water, dried and concentrated. The crude product waschromatographed on silica gel, eluting with 2% ethyl acetate inmethylene chloride. The solvent was removed and the product dried toafford 0.473 g of the title compound, which was taken directly to thenext step.

Example 334B(2S,3S,5S)-2,5-Bis-(N-(isoxazol-5-ylmethoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

A 125.8 mg (0.476 mmol) sample of the compound from Example 334B abovewas added to 45 mg (0.159 mmol) of the product of Example 1E in 0.5 mLof DMF and stirred for 16 hours. The solvent was removed and the crudeproduct chromatographed on silica gel, eluting with 20% ethyl acetate inmethylene chloride. The solvent was removed and the product dried toafford 30.6 mg of the title compound. MS M/Z (DCI/NH₃): 552 (m+H₂ O),535 (M+H). Proton NMR (DMSO): δ1.5 (t, 2H), 2.65-2.77 (4H), 3.57 (m,1H), 3.86 (br, 2H), 4.71 (d, 1H), 4.95-5.12 (4H), 6.32 (m, 2H),7.07-7.34 (12H), 8.53 (d, 2H). Anal calc. for C₂₈ H₃₀ N₄ O₇.1/3H₂ O: C,62.22; H, 5;68; N, 10.37; found: C, 62.06; H, 5.63; N, 10.33.

Example 335 (2S, 3S,5S)-2,5-Bis-(N-(2-hydroxyethoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneExample 335A1-(t-Butyldimethylsilyloxy)-2-(p-nitrophenoxycarbonyloxy)ethane

A 604 mg (3.00 mmol) sample of p-nitrophenoxycarbonylchloride in 3 mL ofmethylene chloride was added to a solution of 0.528 g (3.00 mmol) of2-(t-butyldimethylsilyloxy)ethanol and 0.330 mL of 4-methylmorpholine in2 mL of methylene chloride cooled in an ice bath. The solution wasstirred for 2 hours. The mixture was diluted with methylene chloride,which was washed with water, dried and concentrated. The crude productwas chromatographed on silica gel, eluting with 10% ethyl acetate inhexane. The solvent was removed and the product dried to afford 0.453 gof the title compound, which was taken directly to the next step.

Example 335B(2S,3S,5S)-2,5-Bis-(N-(2-(t-butyldimethylsilyloxy)ethoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

A 328 mg (0.961 mmol) sample of the compound from Example 335A above wasadded to 91 mg (0.32 mmol) of the product of Example 1E in 0.8 mL of DMFand stirred for 16 hours. The solvent was removed and the crude productchromatographed on silica gel, eluting with 50% ethyl acetate in hexane.The product was rechromatographed on silica gel, eluting with 2% and 10%ethyl acetate in methylene chloride. The solvent was removed and theproduct dried to afford 100 mg of the title compound. This material wastaken directly to the next step.

Example 335C(2S,3S,5S)-2,5-Bis-(N-(2-hydroxyethoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

In two batches, 81.4 mg (0.016 mmol) of the compound from Example 335Babove was dissolved in 2 mL of methanol to which 14.9 μL oftrimethylsilyl chloride was added and stirred for 2 hours. The solventwas removed and the crude product chromatographed on silica gel, elutingwith 2% and 5% methanol in methylene chloride. The solvent was removedand the product dried to afford 42.6 mg of the title compound. MS M/Z(DCI/NH₃): 461 (M+H), 478 (M+NH₄). Proton NMR (DMSO): δ1.46 (t, 2H),2.53-2.77 (4H), 3.45 (m, 3H), 3.55 (d, 1H), 3.64-3.92 (6H), 4.64 (m,2H), 6.65 (d, 1H), 6.94 (d, 1H), 7.07-7.27 (10H). Anal calc. for C₂₄ H₃₂N₂ O₇.H₂ O: C, 60.25; H, 7.11; N, 5.86; found: C, 60.38; H, 6.56; N,5.86.

Example 336 (2S, 3S,5S)-2,5-Bis-(N-(2,5-dihydrofuran-3-yl-methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneExample 336A 3-((t-butyldimethylsilyloxy)methyl)-4-hydroxybut-2-eneoicacid, 1,4-lactone

A 2.960 g (196 mmol) sample of t-butyldimethylsilyl chloride was addedto a solution of 1 86 g (163 7 mmol) of3-hydroxymethyl-4-hydroxybut-2-eneoic acid, 1,4-lactone and 2.783 g(40.9 mmol) of imidazole in 6 mL of DMF. The mixture was stirred for 5.5hours. The mixture was diluted with water and extracted with ethylacetate. The solvent was removed and the residue was chromatographed ona silica gel column, eluting with 20% ethyl acetate in hexane. Thesolvent was removed and the product dried to afford 3.109 g of the titleproduct.

Example 336B 2-((t-Butyldimethylsilyloxy)methyl)-but-2-ene-1,4-diol

A 2.210 g (9.69 mmol) sample of3-((t-butyldimethylsilyloxy)methyl)-4-hydroxybut-2-eneoic acid,1,4-lactone, from Example 336A, was dissolved in 6 mL of methylenechloride, cooled in a dry ice bath, and 14.2 mL (21.3 mmol) of DIBAL wasadded. The mixture was stirred at -78° C. for 4 hours, allowed to warmto room temperature and stirred for 16 hours. The mixture was cooled to-78° C. and quenched with 1.53 mL of methanol and 2.55 mL of water. Themixture was filtered, and the filtrate concentrated and chromatographedon silica gel, eluting with 50% and 90% ethyl acetate in hexane. Thesolvent was removed and the product dried to afford 1.055 g of the titleproduct, which was taken directly to the next step.

Example 336C 3-t-Butyldimethylsilyloxy)methyl-2,5-dihydrofuran

To a 0.792 g sample of the compound from Example 336B above in 5 mL ofmethylene chloride was added a solution of 4.59 g (6.53 mmol) ofMartin's Sulfurane (Aldrich) in methylene chloride. The solution wasstirred for 3.25 hours, diluted, washed with 20% KOH and saturatedbrine, dried and concentrated. The residue was chromatographed on silicagel, eluting with 10% ethyl acetate in hexane. The solvent was removedand the product dried to afford 0.282 g of the title product, which wastaken directly to the next step.

Example 336D 3-hydroxymethyl -2,5-dihydrofuran

To a 0.270 g (1.26 mmol) sample of the compound from Example 336C abovedissolved in 2 mL of methanol was added 0.160 mL (1.26 mmol) oftrimethylsilyl chloride The solution was sitted for 2.25 hours, thesolvent was removed, and the residue chromatographed on a silica gelcolumn, eluting with 50% and 90% ethyl acetate in hexane. The solventwas removed and the product dried to afford 65 mg of the title compound,which was taken directly to the next step.

Example 336E 3-p-nitrophenoxycarbonyloxymethyl-2,5-dihydrofuran

To 65 mg (0.65 mmol) of the compound from Example 336D in methylenechloride was added 0.079 mL of 4-methylmorpholine and 144 mg (0.715mmol) of p-nitrophenoxycarbonylchloride. The mixture was stirred for 2hours, diluted with solvent, washed with saturated brine, and thesolvent removed. The residue was chromatographed on a silica gel column,eluting with 20% and 30% ethyl acetate in hexane. The solvent wasremoved and the product dried to afford 0.115 g of the title product.

Example 336F (2S,3S,5S)-2,5-Bis-(N-(2,5-dihydrofuran-3-yl-methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

A 0.110 g (0.415 mmol) sample of the compound from Example 336D aboveand 47 mg (0.166 mmol) of the product of Example 1E were stirred in 0.80mL of DMF for 16 hours. The solvent was removed, and the residue waschromatographed on a silica gel column, eluting with 20% and 50% ethylacetate in methylene chloride. The solvent was removed and the productdried to afford 34.8 mg of the title compound. MS M/Z (DCI/NH₃): 537(M+H), 554 (M+NH₄). Proton NMR (DMSO): δ1.48 (t, 2H), 2.62-2.72 (4H),3.56 (m, 1H), 3.78-3.93 (2H), 4.36 (br, 4H), 4.47 (br, 8H), 4.68 (d,1H), 5.67 (s, 2H), 6.82 (d, 1H), 7.05-7.25 (11H).

Example 337(2S,3S,5S)-2,5-Bis-(N-(3-hydroxy-1-propoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexaneExample 337A1-(t-Butyldimethylsilyloxy)-3-(p-nitrophenoxycarbonyloxy)propane

A 0.604 g (3.00 mmol) sample of p-nitrophenoxycarbonylchloride in 3 mLof methylene chloride was added to a solution of 0.570 g (3.00 mmol) of3-(t-butyldimethylsilyloxy)-1-propanol and 0.329 mL of4-methylmorpholine in 2 mL of methylene chloride cooled in an ice bath.The solution was stirred for 2 hours. The mixture was diluted withmethylene chloride, which was washed with water, dried and concentrated.The crude product was chromatographed on silica gel, eluting with 10%ethyl acetate in hexane. The solvent was removed and the product driedto afford 0.831 g of the title compound, which was taken directly to thenext step.

Example 337B2,5-Bis-(N-(3-(t-butyldimethylsilyloxy)-1-propoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

A 328 mg (0.961 mmol) sample of the compound from Example 337A above wasadded to 105 mg (0.32 mmol) of the product of Example 1E in 1.2 mL ofDMF and stirred for 16 hours. The solvent was removed and the crudeproduct chromatographed on silica gel, eluting with 50% ethyl acetate inhexane. The product was rechromatographed on silica gel, eluting with10% and 20% ethyl acetate in methylene chloride. The solvent was removedand the product dried to afford 185 mg of the title compound. Thismaterial was taken directly to the next step.

Example 337C (2S,3S,5S)-2,5-Bis-(N-(3-hydroxy-1-propoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane

A 0.170 g (0.237 mmol) of the compound from Example 337B above wasdissolved in 2 mL of methanol to which 30 μL of trimethylsilyl chloridewas added and stirred for 2.25 hours. The solvent was removed and thecrude product chromatographed on silica gel, eluting with 2% and 5%methanol in methylene chloride. The solvent was removed and the productdried to afford 22.7 mg of the title compound. MS M/Z (DCI/NH₃): 489(M+H), 506 (M+NH₄). Proton NMR (DMSO): δ1.45 (t, 2H), 1.60 (m, 4H),2.55-2.75 (4H), 3.40 (m, 2H), 3.55 (br, 1H), 3.74-3.96 (8H), 4.44 (t,2H), 4.62 (d, 1H), 6.63 (d, 1H), 6.89 (d, 1H),7.07-7.27 (10H).

Fluorogenic Assay for Screening Inhibitors of HIV Protease

The inhibitory potency of the compounds of the invention can bedetermined by the following method.

A compound of the invention is dissolved in DMSO and a small aliquotfurther diluted with DMSO to 100 times the final concentration desiredfor testing. The reaction is carried out in a 6×50 mm tube in a totalvolume of 300 microliters. The final concentrations of the components inthe reaction buffer are: 125 mM sodium acetate, 1M sodium chloride, 5 mMdithiothreitol, 0.5 mg/ml bovine serum albumin, 1.3 μM fluorogenicsubstrate, 2% (v/v) dimethylsulfoxide, pH 4.5. After addition ofinhibitor, the reaction mixture is placed in the fluorometer cell holderand incubated at 30° C. for several minutes. The reaction is initiatedby the addition of a small aliquot of cold HIV protease. Thefluorescence intensity (excitation 340 nM, emmision 490 nM) is recordedas a function of time. The reaction rate is determined for the first sixto eight minutes. The observed rate is directly proportional to themoles of substrate cleaved per unit time. The percent inhibition is100×(1-(rate in presence of inhibitor)/(rate in absence of inhibitor)).

Fluorogenic substrate: Dabcyl-Ser-Gln-Asn-Tyr-Pro-Ile-Val-Gln-EDANSwherein DABCYL=4-(4-dimethylaminophenyl)azobenzoic acid andEDANS=5-((2-aminoethyl)amino)naphthalene-1-sulfonic acid.

Table 1 shows the inhibitory potencies of compounds of the inventionagainst HIV-1 protease.

                  TABLE 1    ______________________________________                           Inhibitor    Compound of   Percent  Concentration    Example       Inhibition                           (nanomolar)    ______________________________________     37C          61       1     38           55       0.5     39           61       0.5     40           61       0.5    171           62       0.5    174           51       0.5    290           65       0.5    297           43       0.5    298           56       0.5    305           91       0.5    306           88       0.5    307           64       0.5    308           67       0.5    309           97       0.5    310           83       0.5    311           84       0.5    312           84       0.5    314           63       0.5    315           80       0.5    319           52       0.5    320           60       0.5    321           64       0.5    322B          72       0.5    326           66       0.5    327           69       0.5    334B          56       1.0    ______________________________________

Antiviral Activity

The anti-HIV activity of the compounds of the invention can bedetermined in MT4 cells according to the procedure of Pauwels et. al.(J. Virol. Methods 1988, 20, 309). The IC₅₀ is the concentration ofcompound that gives 50% inhibition of the cytopathic effect of HIV. TheLC₅₀ is the concentration of compound at which 50% of the cells remainviable.

Table 2 shows the inhibitory potencies of compounds of the inventionagainst HIV-1_(3B) in MT4 cells.

                  TABLE 2    ______________________________________    Compound of   IC.sub.50  LC.sub.50    Example       (micromolar)                             (micromolar)    ______________________________________     37C          0.84-1.44  >100     38           0.55-0.61  >100     39           0.13-0.25  >100     40           0.23-0.55  64    171           0.38-0.55  >100    174           0.14-0.23  >100    290           0.026-0.075                             >100    297           0.31-0.35  81    298           0.22-0.29  59    305           0.005-0.017                             >100    306           0.007-0.019                             >100    307           0.16-0.26  >100    308           0.077-0.124                             96    310           0.013-0.025                             55    311           0.058-0.067                             58    312           0.058-0.077                             61    313           0.46-0.5   >100    314           0.098-0.144                             >100    315           0.003-0.005                             >100    319           0.21-0.29  >100    320           0.4-0.5    >100    321           0.14-0.19  >100    322B          0.086-0.094                             >100    326           0.053-0.086                             27    327           0.034-0.064                             84    334B          0.74-1.6   91    ______________________________________

The compounds of the present invention can be used in the form of saltsderived from inorganic or organic acids. These salts include but are notlimited to the following: acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate,ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxy-ethanesulfonate (isethionate), lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such and butyl chloride, bromides, and iodides; dialkylsulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides, aralkyl halides like benzyl and phenethylbromides, and others. Water or oil-soluble or dispersible products arethereby obtained.

Examples of acids which may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulphuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, succinic acid and citric acid. Othersalts include salts with alkali metals or alkaline earth metals, such assodium, potassium, calcium or magnesium or with organic bases.

Preferred salts of the compounds of the invention include hydrochloride,methanesulfonate, sulfonate, phosphonate and isethionate.

The compounds of the present invention can also be used in the form ofesters. Examples of such esters include a hydroxyl-substituted compoundof formula I which has been acylated with a blocked or unblocked aminoacid residue, a phosphate function, a hemisuccinate residue, an acylresidue of the formula R*C(O)-- or R*C(S)-- wherein R* is hydrogen,loweralkyl, haloalkyl, alkoxy, thioalkoxy, alkoxyalkyl, thioalkoxyalkylor haloalkoxy, or an acyl residue of the formula R_(a)--C(R_(b))(R_(d))--C(O)-- or R_(a) --C(R_(b))(R_(d))--C(S)-- whereinR_(b) and R_(d) are independently selected from hydrogen or loweralkyland R_(a) is --N(Re)(R_(f)), OR_(e) or --SR_(e) wherein R_(e) and R_(f)are independently selected from hydrogen, loweralkyl and haloalkyl, oran amino-acyl residue of the formula R₁₈₀ NH(CH₂)₂ NHCH₂ C(O)-- Or R₁₈₀NH(CH₂)₂₀ CH₂ C(O)-- wherein R₁₈₀ is hydrogen, loweralkyl, arylalkyl,cycloalkylalkyl, alkanoyl, benzoyl or an α-amino acyl group. The aminoacid esters of particular interest are glycine and lysine; however,other amino acid residues can also be used, including those wherein theamino acyl group is --C(O)CH₂ NR₂₀₀ R₂₀₁ wherein R₂₀₀ and R₂₀₁ areindependently selected from hydrogen and loweralkyl or the group --NR₂₀₀R₂₀₁ forms a nitrogen containing heterocyclic ring. These esters serveas pro-drugs of the compounds of the present invention and serve toincrease the solubility of these substances in the gastrointestinaltract. These esters also serve to increase solubility for intravenousadministration of the compounds. Other prodrugs include ahydroxyl-substituted compound of formula I wherein the hydroxyl group isfunctionalized with a substituent of the formula --CH (R_(g))OC(O) R₁₈₁or --CH (R_(g))OC(S)R₁₈₁ wherein R₁₈₁ is loweralkyl, haloalkyl, alkoxy,thioalkoxy or haloalkoxy and R_(g) is hydrogen, loweralkyl, haloalkyl,alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl ordialkylaminocarbonyl. The prodrugs of this invention are metabolized invivo to provide the hydroxyl-substituted compound of formula I. Thepreparation of the prodrug esters is carried out by reacting ahydroxyl-substituted compound of formula I with an activated amino acyl,phosphoryl, hemisuccinyl or acyl derivative as defined above. Theresulting product is then deprotected to provide the desired pro-drugester. Prodrugs of the invention can also be prepared by alkylation ofthe hydroxyl group with (haloalkyl)esters, transacetalization withbis-(alkanoyl)acetals or condensation of the hydroxyl group with anactivated aldehyde followed by acylation of the intermediate hemiacetal.

The compounds of the invention are useful for inhibiting retroviralprotease, in particular HIV protease, in vitro or in vivo. The compoundsof the present invention are also useful for the treatment orprophylaxis of diseases caused by retroviruses, especially acquiredimmune deficiency syndrome or an HIV infection in a human or othermammal.

Total daily dose administered to a human or other mammal host in singleor divided doses may be in amounts, for example, from 0.001 to 300 mg/kgbody weight daily and more usually 0.1 to 10 mg. Dosage unitcompositions may contain such amounts of submultiples thereof to make upthe daily dose.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, rate of excretion, drug combination, and the severity ofthe particular disease undergoing therapy.

The compounds of the present invention may be administered orally,parenterally, sublingually, by inhalation spray, rectally, or topicallyin dosage unit formulations containing conventional nontoxicpharmaceutically acceptable carriers, adjuvants, and vehicles asdesired. Topical administration may also involve the use of transdermaladministration such as transdermal patches or iontophoresis devices. Theterm parenteral as used herein includes subcutaneous injections,intravenous, intramuscular, intrasternal injection, or infusiontechniques.

Injectable preparations, for example, sterile injectable aqueous oroleagenous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-propanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable nonirritating excipient such as cocoabutter and polyethylene glycols which are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose lactose or starch. Such dosage forms may also comprise, as isnormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, and sweetening, flavoring, andperfuming agents.

The compounds of the present invention can also be administered in theform of liposomes. As is known in the art, liposomes are generallyderived from phospholipids or other lipid substances. Liposomes areformed by mono- or multi-lamellar hydrated liquid crystals that aredispersed in an aqueous medium. Any non-toxic, physiologically aceptableand metabolizable lipid capabale of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition no acompound of the present invention, stabilizers, preservatives,excipients, and the like. The preferred lipids are the phospholipids andphosphatidyl cholines (lecithins), both natureal and synthetic.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y. (1976), p. 33 et seq.

While the compounds of the invention can be administered as the soleactive pharmaceutical agent, they can also be used in combination withone or more immunomodulators, antiviral agents, other antiinfectiveagents or vaccines. Other antiviral agents to be administered incombination with a compound of the present invention include AL-721,beta interferon, polymannoacetate, reverse transcriptase inhibitors (forexample, ganciclovir, dideoxycytidine (DDC), dideoxyinosine (DDI),BCH-189, AzdU, carbovir, DDA, D4C, D4T, DP-AZT, FLT (fluorothymidine),BCH-189, 5-halo-3'-thiadideoxycytidine, PMEA, zidovudine (AZT) and thelike), non-nucleoside reverse transcriptase inhibitors (for example,R82193, L-697,661, BI-RG-587 (nevirapine), HEPT compounds, L,697,639,R82150, U-87201E and the like), TAT inhibitors (for example, RO-24-7429and the like), trisodium phosphonoformate, HPA-23, eflonithine, PeptideT, Reticulose (nucleophosphoprotein), ansamycin LM 427, trimetrexate,UA001, ribavirin, alpha interferon, oxetanocin, oxetanocin-G, cylobut-G,cyclobut-A, ara-M, BW882C87, foscarnet, BW256U87, BW348U87, BV ara-U,CMV triclonal antibodies, FIAC, HOE-602, HPMPC, MSL-109, TI-23,trifluridine, vidarabine, famciclovir, penciclovir, acyclovir,castanospermine, rCD4/CD4-IgG, CD4-PE40, butyl-DNJ, hypericin,oxamyristic acid, dextran sulfate and pentosan polysulfate.Immunomodulators that can be administered in combination with a compoundof the present invention include bropirimine, Ampligen, anti-human alphainterferon antibody, colony stimulting factor, CL246,738, Imreg-1,Imreg-2, diethydithiocarbamate, interleukin-2, alpha-interferon, inosinepranobex, methionine enkephalin, muramyl-tripeptide, TP-5,erythropoietin, naltrexone, tumor necrosis facator, beta interferon,gamma interferon, interleukin-4, autologous CD8+ infusion, alphainterferon immunoglobulin, anti-Leu-3A, autovaccination, biostimulation,extracorporeal photophoresis, FK-565, FK-506, G-CSF, GM-CSF,hyperthermia, isopinosine, IVIG, passisve immunotherapy and poliovaccine hyperimmunization. Other antiinfective agents that can beadministered in combination with a compound of the present inventioninclude pentamidine isethionate. Any of a variety of HIV or AIDSvaccines (for example, gp120 (recombinant), Env 2-3 (gp120), HIVAC-1e(gp120), gp160 (recombinant), VaxSyn HIV-1 (gp160), Immuno-Ag (gp160),HGP-30, HIV-Immunogen, p24 (recombinant), VaxSyn HIV-1 (p24) can be usedin combination with a compound of the present invention.

Other agents that can be used in combination with the compounds of thisinvention are ansamycin LM 427, apurinic acid, ABPP, A1-721, carrisyn,AS-101, avarol, azimexon, colchicine, compound Q, CS-85, N-acetylcysteine (2-oxothiazolidine-4-carboxylate), D-penicillamine,diphenylhydantoin, EL-10, erythropoieten, fusidic acid, glucan, HPA-23,human growth hormone, hydorxchloroquine, iscador, L-ofloxacin or otherquinolone antibiotics, lentinan, lithium carbonate, MM-1, monolaurin,MTP-PE, naltrexone, neurotropin, ozone, PAI, panax ginseng,pentofylline, Peptide T, pine cone extract, polymannoacetate,reticulose, retrogen, ribavirin, ribozymes, RS-47, Sdc-28,silicotungstate, THA, thymic humoral factor, thymopentin, thymosinfraction 5, thymosin alpha one, thymostimulin, UA001, uridine, vitaminB12 and wobemugos.

Other agents that can be used in combination with the compounds of thisinvention are antifungals such as amphotericin B, clotrimazole,flucytosine, fluconazole, itraconazole, ketoconazole and nystatin andthe like.

Other agents that can be used in combination with the compounds of thisinvention are anitbacterials such as amikacin sulfate, azithromycin,ciprofloxacin, temafloxacin, tosufloxacin, clarithromycin, clofazimine,ethambutol, isoniazid, pyrazinamide, rifabutin, rifampin, streptomycinand TLC G-65 and the like.

Other agents that can be used in combination with the compounds of thisinvention are anti-neoplastics such as alpha interferon, COMP(cyclophosphamide, vincristine, methotrexate and prednisone), etoposide,mBACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide,vincristine and dexamethasone), PRO-MACE/MOPP(prednisone, methotrexate(w/leucovin rescue), doxorubicin, cyclophosphamide,etoposide/mechlorethamine, vincristine, prednisone and procarbazine),vincristine, vinblastine, angioinhibins, pentosan polysulfate, plateletfactor 4 and SP-PG and the like.

Other agents that can be used in combination with the compounds of thisinvention are drugs for treating neurological disease such as peptide T,ritalin, lithium, elavil, phenytoin, carbamazipine, mexitetine, heparinand cytosine arabinoside and the like.

Other agents that can be used in combination with the compounds of thisinvention are anti-protozoals such as albendazole, azithromycin,clarithromycin, clindamycin, corticosteroids, dapsone, DIMP,eflornithine, 566C80, fansidar, furazolidone, L, 671,329, letrazuril,metronidazole, paromycin, pefloxacin, pentamidine, piritrexim,primaquine, pyrimethamine, somatostatin, spiramycin, sulfadiazine,trimethoprim, TMP/SMX, trimetrexate and WR 6026 and the like.

Among the preferred agents for treatment of HIV or AIDS in combinationwith the compounds of this invention are reverse transcriptaseinhibitors.

It will be understood that agents which can be combined with thecompounds of the present invention for the treatment or prophylaxis ofAIDS or an HIV infection are not limited to those listed above, butinclude in principle any agents useful for the treatment or prophylaxisof AIDS or an HIV infection.

When administered as a combination, the therapeutic agents can beformulated as separate compositions which are given at the same time ordifferent times, or the therapeutic agents can be given as a singlecomposition.

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims.

What is claimed is:
 1. A compound of the formula: ##STR17##